Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version.

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TITLE PAGE

Oxidative Stress and Response to Thymidylate Synthase-Targeted

Antimetabolites

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Ufuk Ozer, Karen W. Barbour, Sarah A. Clinton, and Franklin G. Berger

Department of Biological Sciences, University of South Carolina, Columbia, SC (U.O., K.W.B., molpharm.aspetjournals.org S.A.C., F.G.B), and Center for Colon Cancer Research, University of South Carolina, Columbia,

SC (U.O., K.W.B., S.A.C., F.G.B)

at ASPET Journals on October 2, 2021

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RUNNING TITLE PAGE

Running title: Oxidative Stress and Thymidylate Synthase Inhibitors

Address correspondence to: Dr. Franklin G. Berger, Center for Colon Cancer Research,

University of South Carolina, Columbia, SC 29208. TEL: 803-777-1231; FAX: 803-777-1173; Downloaded from

EMAIL: [email protected]

molpharm.aspetjournals.org Number of text pages: 37

Number of tables: 3

Number of figures: 8

Number of references: 36 at ASPET Journals on October 2, 2021

Number of words in the Abstract: 197

Number of words in the Introduction: 457

Number of words in the Discussion: 1,289

ABBREVIATIONS: APO, apocyanin; DCFDA, 2',7'-dichlorodihydrofluorescein diacetate;

DHE, dihydroethidium; DPI, diphenyleneiodonium; dThd, deoxythymidine; FdUrd, 5-fluoro-2’-

deoxyuridine; FDXR, ferredoxin reductase; FUra, 5-; NAC, N-acetylcysteine; NOX,

●- NADPH oxidase; NRF2, nuclear factor E2-related factor 2; O2 , superoxide; ROS, reactive

species; RTX, ; siRNAs, Small interfering ; TYMS, Thymidylate synthase; VAS, VAS2870.

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ABSTRACT

Thymidylate synthase (TYMS; EC 2.1.1.15) catalyzes the reductive of dUMP by N5,N10-methyhlenetetrahydrofolate, forming dTMP for the maintenance of DNA replication and repair. Inhibitors of TYMS have been widely used in the treatment of neoplastic

disease. A number of fluoropyrimidine and analogs have been developed that lead to Downloaded from inhibition of the , resulting in dTMP deficiency and cell death. In the current study, we have examined the role of oxidative stress in response to TYMS inhibitors. We observed that molpharm.aspetjournals.org intracellular reactive oxygen species (ROS) concentrations are induced by these inhibitors, and promote apoptosis. Activation of the enzyme NADPH oxidase (NOX), which catalyzes one-

●- electron reduction of O2 to generate superoxide (O2 ), is a significant source of increased ROS

levels in drug-treated cells. However, expression profiling revealed a number of other at ASPET Journals on October 2, 2021 redox-related that may contribute to ROS generation. TYMS inhibitors also induce a protective response, including activation of the factor nuclear factor E2-related factor 2 (NRF2), a critical mediator of protection against oxidative and electrophilic stress. Our results show that exposure to TYMS inhibitors induces oxidative stress that leads to cell death, while simultaneously generating a protective response that may underlie resistance against such death.

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Introduction

Thymidylate synthase (TS; EC 2.1.1.15) catalyzes the reductive methylation of dUMP by

5 10 N N -methylenetetrahydrofolate (CH2H4PteGlu), to form dTMP and dihydrofolate (Berger and

Berger, 2006; Carreras and Santi, 1995). The enzyme is indispensable to DNA synthesis, and is

therefore critical for replication and repair of the cellular genome in growing cells. As a

consequence, it has been an attractive target at which chemotherapeutic drugs are directed (Chu Downloaded from

et al., 2003; Longley et al., 2003; Wilson et al., 2014). Inhibitors of TYMS, including both fluoropyrimidine and folate analogues, reduce de novo synthesis of dTMP, which leads to molpharm.aspetjournals.org impaired DNA replication, genome damage, and programmed cell death (Barbour and Berger,

2008; Berger and Berger, 2006; Carreras and Santi, 1995). Fluoropyrimidines such as 5- fluorouracil (FUra) and 5-fluoro-2’-deoxyuridine (FdUrd) are metabolized within cells to the

potent TYMS inhibitor 5-fluoro-2’-deoxyuridylic acid (FdUMP), and have been important in the at ASPET Journals on October 2, 2021 therapy of a variety of cancers, including those of the ovary, breast, and gastrointestinal tract

(Chu et al., 2003; Longley et al., 2003). Folate-based inhibitors of TYMS have been designed on the basis of information from the structures of the natural substrates and the enzyme’s cleft (Bertino, 1997; Carreras and Santi, 1995; Takemura and Jackman, 1997). Indeed, these inhibitors were among the first to be developed using such rationally-based criteria. Several, including raltitrexed (RTX), LY231514, ZD9331, and GW1843U89, have advanced to clinical trials, and have demonstrated significant activity against a variety of neoplasms (Bertino, 1997;

Takemura and Jackman, 1997).

The mechanism by which dTMP deficiencies lead to the death of cells exposed to TYMS inhibitors is of central interest. Over a decade ago, Hwang et al. (Hwang et al., 2001) demonstrated that induction of reactive oxygen species (ROS) in FUra-treated cells results from

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increased expression of the mitochondrial enzyme ferredoxin reductase (FDXR), and is required

for p53-dependent apoptotic response to drug. Studies by Liu and Chen similarly suggested that

FDXR promotes ROS-mediated apoptosis in response to FUra in a p53-dependent fashion (Liu and Chen, 2002). Despite these interesting studies, as well as others showing increased ROS levels following exposure to FUra (Akhdar et al., 2009; Lamberti et al., 2012; Matsunaga et al.,

2010), we still lack a detailed mechanistic understanding of how exposure to TYMS inhibitors Downloaded from

alters the intracellular redox environment, and how cells respond to such alterations. Currently, we have examined ROS-mediated oxidative stress and its function in apoptotic cell death molpharm.aspetjournals.org induced by TYMS inhibitors. We have identified the superoxide-generating enzyme NADPH oxidase (NOX) as an important source of increased ROS levels during drug exposure. In addition, we have found that cells mount a protective response that includes activation of the

nuclear factor E2-related factor 2 (NRF2) and its downstream target genes, at ASPET Journals on October 2, 2021 which may diminish the cytotoxic impact of TYMS inhibitors.

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Materials and Methods

Reagents. FUra, FdUrd, deoxythymidine (dThd), , and N-acetylcysteine

(NAC) were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). RTX was obtained from

AstraZeneca (Macclesfield, Cheshire, UK). Diphenyleneiodonium (DPI) and NADPH were

purchased from Calbiochem/EMD Biosciences (San Diego, CA, USA). APO was from Acros

Organics Inc. (Geel, Belgium). Lucigenin and VAS2870 (VAS) were from Enzo Life Sciences Downloaded from

Inc. (Plymouth Meeting, PA, USA). Paraformaldehyde was from Alfa Aesar (Ward Hill, MA,

USA). DHE and H2DCFDA were purchased from Invitrogen/Molecular Probes Inc. (Eugene, molpharm.aspetjournals.org OR, USA). Oligonucleotides were purchased from Integrated DNA Technologies Inc.

(Coralville, IA, USA).

Cell culture. Human colon tumor cell line HCT116 (originally obtained from Dr.

Michael G. Brattain), FdUrd-resistant HCT116/200 (Berger et al., 1988), HCT-15 (American at ASPET Journals on October 2, 2021

Tissue Culture Collection, Manassas, VA, USA), and SW480 (American Tissue Culture

Collection, Manassas, VA, USA) were maintained in RPMI-1640 medium (Mediatech Inc,

Manassas, VA, USA) containing 4.5 g/l glucose and supplemented with 10% heat-inactivated

fetal bovine serum (Atlanta Biologicals, Norcross, GA, USA), 100 U/mL penicillin, 100 mg/mL

streptomycin and 250 ng/mL amphotericin B (Mediatech Inc) at 37°C in a humidified 5% CO2

atmosphere. Cells were exposed to the indicated concentrations of TYMS inhibitors (FUra,

FdUrd, RTX) based upon previous studies in our laboratory (Barbour and Berger, 2008); 10 µM

folinic acid was included with FdUrd. Where indicated, NAC (10 mM), dThd (10 µM), DPI (10

µM), APO (1 mM), or VAS (10 µM) were included in the culture medium; all were added along with TYMS inhibitors, while DPI was added 3 h prior to addition of TYMS inhibitors.

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Detection of ROS. Intracellular ROS production was measured by oxidation of cell permeable dyes 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) to detect H2O2 and

●- dihydroethidium (DHE) to detect O2 . Cells were grown to 60% confluence in chamber slides,

fixed in 4% paraformaldehyde, and incubated at 37°C for 30 min in 5 µM DCFDA or DHE.

After incubation, cells were washed twice with PBS and imaged by fluorescence microscopy

(Carl Zeiss) using a charge-coupled camera (AxioCam HRm) linked to AxioVision software Downloaded from

(version 4.7).

For measurement of ROS by flow cytometry, cells were grown to 80% confluence in molpharm.aspetjournals.org 60mm plates and incubated in fluorescence-activated cell-sorting (FACS) staining buffer (PBS with 1% BSA) at 37°C for 15 min in 50 nM DCFDA or DHE. After incubation, cells were washed twice with FACS buffer and analyzed by flow cytometry (FC 500, Beckman Coulter,

Fort Collins, CO, USA). A shift to the right indicates increased ROS levels. at ASPET Journals on October 2, 2021

Measurement of apoptotic cell death. Cells were treated with TYMS inhibitors and inhibitory agents at the indicated concentrations for 48 h. Apoptotic indices were determined by

TUNEL assays using the In Situ Cell Death Detection Kit, POD (Roche Applied Science,

Indianapolis, IN, USA). Cells were stained according to the manufacturer’s instructions, counterstained with hematoxylin, and viewed under a light microscope at 400X magnification.

Apoptotic nuclei were counted manually, based on staining and morphology, and the apoptotic index was calculated as the ratio of apoptotic/total cells. At least 1,000 cells from several microscopic fields were counted in each determination.

NADPH oxidase activity assay. For each reaction, 105 cells were suspended in 500 µl

reaction buffer [50 mM phosphate buffer (pH 7.0), 1 mM EGTA, 150 mM sucrose]. NADPH

oxidase activity was detected by lucigenin-derived chemiluminescence with 100 µM NADPH as

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and 5 µM lucigenin. Cells were incubated at 37°C for 10 min. Chemiluminescence

was measured using a luminometer (Promega, Madison WI, USA) and expressed as arbitrary

light units per 105 cells.

RNA extraction and qPCR. Total RNA was isolated using RNeasy Mini Kit (Qiagen,

Maryland, USA) with the addition of RNase Free DNase (Qiagen) to eliminate contaminating

genomic DNA. The RNA concentration was determined by measuring the absorbance at 260 nm Downloaded from

and 280 nm (NanoDrop ND-1000 Spectrophotometer, Thermo Fisher Scientific, USA). For each

reaction, 1µg RNA was reverse transcribed using an IScript cDNA synthesis kit (Bio-Rad, molpharm.aspetjournals.org Hercules, CA, USA) according to the manufacturer’s instructions. For quantitative PCR (qPCR), cDNA (1μl) prepared as described above was amplified using Power SYBR Green PCR Master

Mix (Applied Biosystems, Foster City, CA, USA) according to the manufacturer’s instructions.

The PCR thermal profile was one cycle at 95°C for 10 min followed by 40 cycles of 95°C for 15 at ASPET Journals on October 2, 2021

s, 50°C for 15 s, and 72°C for 40 s using an Applied Biosystems 7300 Real Time PCR System.

Relative mRNA levels were normalized to GAPDH, and calculated by the 2−ΔΔCt method.

Relative changes in expression of each gene in response to TYMS inhibitors were expressed as

fold-induction compared with the basal level of expression in non-treated cells. Gene-specific

primer sets (Integrated DNA Technologies, Coralville, IA, USA) used for qPCR are listed in

Table 1. Controls with no and no template RNA were used to monitor

contamination.

Transfection of small-interfering RNAs. Small-interfering RNAs (siRNAs) were

introduced into cells by transient transfection using the DharmaFECT 4 reagent (GE Dharmacon,

Lafayette, CO, USA) in accordance with the manufacturer’s instructions. HCT116 cells were

transfected with ON-TARGETplus siRNA for NOX2 (Dharmafect J-011021-05-0005), NRF2

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(Dharmafect J-003755-09-0005), or scrambled siRNA (Dharmafect D-001810-01-05) as a

negative control. Twenty-four hours post-transfection, cells were treated with various drug

combinations, and harvested at appropriate times for assays.

Microarray analysis. Whole genome cDNA microarray analyses were performed using

Agilent’s platform. Total RNA samples isolated from HCT116 were treated with FUra for 24 h,

then amplified and labeled using Agilent’s Low Input Quick Amp Labeling Kit (Cat. # 5190- Downloaded from

2306) according to the manufacturer’s recommendations. Briefly, mRNA contained in 200 ng of total RNA was converted into cDNA using a poly-dT primer that also contained the T7 RNA molpharm.aspetjournals.org promoter sequence. Subsequently, T7 RNA polymerase was added to cDNA samples to amplify original mRNA molecules and to simultaneously incorporate cyanine 3- or cyanine 5-labeled CTP (cRNA) into the amplification . In addition, Agilent RNA spike-

in controls (Cat. # 5188-5279) were added to samples prior to cDNA synthesis and were used as at ASPET Journals on October 2, 2021 experimental quality control. In the next step, labeled RNA molecules were purified using

Qiagen’s RNeasy Mini Kit (Cat. # 74104). After spectrophotometric assessment of dye incorporation and cRNA yield, samples were stored at -80°C until hybridization. Labeled cRNA samples were hybridized to Agilent Human GE 4x44K v2 Microarrays (Cat. # G4845A) at 65°C for 17 h using Agilent’s Hybridization Kit (Cat. # 5188-5242) according to the manufacturer’s recommendations. Four (4) control sample replicates were hybridized against four (4) FUra treated sample replicates in a dye swap design. After washes, arrays were scanned using an Agilent DNA Microarray Scanner System (Cat. # G2565CA).

Data was extracted from images with Feature Extractor Software version 10.7.3.1

(Agilent). In this process, background correction using additive and multiplicative detrending algorithms was performed. In addition, linear and LOWESS methods were used for dye

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normalization. Subsequently, data was uploaded into GeneSpring GX version 11.5.1 for

analysis. In this process, data was log2 transformed, quantile normalized and base line

transformed using the median of all samples. Then, data was filtered by flags such that 100% of

the samples in at least one of the two treatment groups have a “detected” flag.

Differentially expressed genes were determined by analysis of the data using an unpaired t-test

statistics that was corrected for multiple testing using the Benjamini-Hochberg algorithm. A Downloaded from

cutoff of 1.5-fold change with a p-value of 0.005 was used. To identify genes involved in redox

, the GO (Gene Ontogeny) and KEGG (Kyoto Encyclopedia of Genes and Genomes) molpharm.aspetjournals.org databases were queried with the terms "dehydro, dehydrog, hydro, hydrog, oxid, oxidase,

oxidation, redox, reduc, reductase"; identified genes were assessed for their presence in the microarray.

Preparation of extracts and Western immunoblotting. Cytoplasmic and nuclear at ASPET Journals on October 2, 2021

extracts were prepared using NE-Per® Nuclear and Cytoplasmic Extraction Reagents

(Thermo Fisher Pierce, Rockford, IL, USA). Cells were harvested by trypsinization, and

separation of cytoplasmic and nuclear fractions was carried out according to the manufacturer’s

instructions, with the following modifications: 1X SDS loading buffer was added directly to the

nuclear pellet at 125 µL/1 X 107 cells, sonicated 3X at 10 s pulses, and loaded on the gel.

Immunoblotting was performed by standard techniques. Following SDS/PAGE, fractionated

were transferred to nitrocellulose membranes, probed with an antibody to NRF2 (Cell

Signaling, Beverly, MA, USA) followed by anti-rabbit IgG-HRP secondary antibody (Bio-Rad,

Hercules, CA, USA). The antigen–antibody complexes were visualized using the ECL®

(enhanced chemiluminescence) kit (GE Healthcare Biosciences, Piscataway, NJ, USA). To

monitor the separation of cytoplasmic and nuclear fractions, and to control for equal loading,

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blots were reprobed with anti-lactate dehydrogenase (Rockland Immunochemicals, Limerick,

PA, USA) followed by anti-goat IgG-HRP secondary antibody (Bio-Rad, Hercules, CA, USA), and anti-lamin (Santa Cruz biotechnology, Inc., Dallas, TX, USA) followed by anti-rabbit IgG-

HRP secondary antibody.

Statistical analysis. Results are reported as the mean ± SEM, based on at least 2-5

independent experiments. Significance was assessed by calculation of two-tailed p-values by an Downloaded from unpaired Student’s t-test. molpharm.aspetjournals.org at ASPET Journals on October 2, 2021

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Results

ROS levels are induced during exposure to TYMS-directed . Several studies have shown that intracellular ROS levels increase in response to FUra (Akhdar et al.,

2009; Hwang et al., 2001; Lamberti et al., 2012; Liu and Chen, 2002; Matsunaga et al., 2010).

However, it has not been determined if such increases are due to inhibition of TYMS, as opposed

to other effects of the . Indeed, FUra is well-known to exert impacts on cellular Downloaded from processes other than thymidylate , such as RNA processing and glycoprotein synthesis (Longley et al., 2003). molpharm.aspetjournals.org We measured the effects of TYMS inhibition on ROS levels in HCT116 cells treated with various concentrations of the TYMS-directed fluoropyrimidine FdUrd. Cells were analyzed by flow cytometry following addition of the ROS-detecting fluorescent dye 2',7'-

dichlorodihydrofluorescein diacetate (DCFDA) to the media. As shown in Fig. 1A, a at ASPET Journals on October 2, 2021 progressive increase in ROS levels over a drug concentration range of 1 nM - 10 µM was observed, with the maximum level being reached at ~1 µM.

To verify and extend these initial findings, we examined the impact of three TYMS- directed antimetabolites, including two fluoropyrimidines (FUra, FdUrd) and a folate analog

(RTX), on intracellular levels of ROS. The concentration of each was based upon earlier studies in our laboratory (Barbour and Berger, 2008). Using both fluorescence microscopy and flow cytometry, we observed marked increases in ROS concentrations in response to each inhibitor

(Fig. 1B). Similar results were obtained with a different fluorescent probe, dihydroethidium

(DHE) (data not shown). Further analyses showed that addition of NAC to the culture media abrogated drug-induced fluorescence (Fig. 1C), indicating that the observed increases in fluorescence indeed reflect augmentation of ROS levels following drug exposure. Furthermore,

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supplementation with dThd caused a loss of drug-mediated ROS induction (Fig. 1D),

demonstrating that dTMP deprivation due to TYMS inhibition is occurring. Finally, ROS levels were profoundly diminished in the TYMS-overproducing cell line HCT116/200 (Fig. 1E), which is resistant to fluoropyrimidines as a consequence of TYMS overproduction derived from amplification of the TYMS gene (Berger et al., 1988). In all, these observations show that ROS

induction in response to TYMS-directed antimetabolites arises from inhibition of TYMS and Downloaded from

reduction in dTMP pools.

FdUrd elicited increased ROS levels in other human colon tumor cell lines, such as HCT- molpharm.aspetjournals.org 15 and SW480 (Fig. 1F and G, respectively). These lines also responded to FUra and RTX (data not shown). Thus, the observed induction of ROS following exposure to TYMS inhibitors is not

a specific property of HCT116 cells, but is broadly observed among distinct colon tumor cell

lines. at ASPET Journals on October 2, 2021

ROS induction by TYMS inhibitors promotes apoptosis. The observed augmentation

of ROS levels in cells treated with TYMS inhibitors may promote oxidative stress that contributes to apoptotic cell death. In previous studies, we utilized TUNEL assays to show that apoptosis is increased by10-20-fold in cells exposed to TYMS inhibitors, and was completely inhibited by the broad-spectrum caspase inhibitor Z-VAD-FMK (Barbour and Berger, 2008).

We assessed the role of ROS in apoptosis induced by TYMS inhibitors. Fig. 2 shows that the apoptotic index rose ~11-17-fold in response to FUra (p = 3.7 x 10-6), FdUrd (p = 2.5 x 10-6), and

RTX (p = 1.6 x 10-5). Furthermore, addition of NAC reduced the index by ~50% (p = 0.017 for

FUra, 4.0 x 10-4 for FdUrd, and 7.0 x 10-4 for RTX), indicating that abrogation of ROS levels

reduces apoptotic response to TYMS inhibitors. Thus, oxidative stress is important to the

cytotoxicity of these inhibitors.

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NADPH oxidase (NOX) contributes to ROS induction following exposure to TYMS inhibitors. Previous studies had indicated that the mitochondrial enzyme ferredoxin reductase

(FDXR) is an important source of expanded ROS pools following exposure to FUra (Hwang et al., 2001; Liu and Chen, 2002). Indeed, gene expression profiling conducted in our laboratory

(described below) identified FDXR mRNA as among the transcripts induced by FUra. However,

given the abundance of genes that function in redox pathways, it is highly likely that there exist Downloaded from additional that generate ROS in response to TYMS inhibitors. We tested the role of

●- one such enzyme, NADPH oxidase (NOX), which catalyzes the formation of superoxide (O2 ) molpharm.aspetjournals.org

via one-electron reduction of O2 . The enzyme, which exists as a membrane-bound, multi-

●- subunit complex whose sole function appears to be generation of O2 (Brandes et al., 2014;

Jiang et al., 2011; Sumimoto, 2008), is activated by a wide variety of chemical, physical, and

inflammatory stress stimuli (Jiang et al., 2011). As such, it is of interest to test the contribution at ASPET Journals on October 2, 2021 of NOX to expanded ROS pools in response to TYMS inhibitors.

We utilized a whole-cell chemiluminescence assay to measure total NOX enzyme activity and the effect of TYMS inhibitors. As shown in Fig. 3A, both FUra and FdUrd elicit a

5-7-fold activation of enzyme activity (p = 2.7 x 10-3 for FUra and 1.6 x 10-3 for FdUrd). To be

assured that NOX is being measured in these assays, we added the NOX inhibitor

diphenyleneiodonium (DPI) (Wind et al., 2010) to the culture medium and observed complete

inhibition of the drug-induced activity (p = 1.6 x 10-3 for FUra and 1.1 x 10-3 for FdUrd) (Fig.

3A). Attenuation of the increase in enzyme activity was also observed in the presence of dThd

(p = 0.024 for FUra and 0.014 for FdUrd), and was significantly reduced in TYMS- overproducing HCT116/200 cells (p = 0.021 for FUra and 8.6 x 10-3 for FdUrd) (Fig. 3A). Thus,

NOX activation in response to TYMS inhibitors is primarily due to inhibition of TYMS.

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We determined whether or not NOX functions in drug-mediated accumulation of ROS.

DPI inhibited ROS induction in response to FUra, FdUrd, and RTX, as measured by fluorescence assays with DCFDA (Fig. 3B). Furthermore, another NOX inhibitor, apocyanin

(APO), which has a mechanism of action distinct from DPI (Aldieri et al., 2008), also prevented

ROS induction by the three TYMS-targeted drugs (Fig. 3B). Because both DPI and APO are

non-specific and exert NOX-independent effects (Aldieri et al., 2008), we tested the impact of Downloaded from

VAS2870 (VAS), a triazolo pyrimidine that exhibits a high degree of specificity for NOX (Wind et al., 2010). VAS, similar to DPI and APO, reduced drug-mediated ROS accumulation (Fig. molpharm.aspetjournals.org 3B). Similar findings as these were made using DHE as the fluorescent probe for ROS detection

(data not shown). These results implicate NOX activation as functioning in augmentation of

ROS levels following exposure to TYMS inhibitors.

We measured the impact of drug-mediated NOX activation on apoptosis. As shown in at ASPET Journals on October 2, 2021

Fig. 4, increases in the apoptotic index following exposure to FUra, FdUrd, or RTX were abolished by both DPI (p = 9.7 x 10-6 for FUra, 1.0 x 10-5 for FdUrd, and 3.4 x 10-5 for RTX) and

APO (p = 4.1 x 10-5 for FUra, 1.1 x 10-5 for FdUrd, and 1.6 x 10-5 for RTX), indicating an important role for NOX in drug response. VAS also abrogated drug-induced increases in apoptosis, but only by ~50% (p = 0.013 for FUra, 0.047 for FdUrd, and 0.063 for RTX) (Fig. 4).

The effect of VAS was consistently less than that of either DPI or APO, which may reflect the fact that the latter two exhibit a broader range of specificity than the former (Aldieri et al., 2008;

Wind et al., 2010). This implies that factors other than NOX may contribute to the apoptotic response to TYMS-targeted agents.

Expression of NOX regulatory subunit p67phox is stimulated by TYMS inhibitors.

The NOX family is organized into a number of distinct multisubunit complexes, each member of

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which is comprised of one of seven known core catalytic subunits along with several regulatory

subunits (Block and Gorin, 2012; Brandes et al., 2014; Sumimoto, 2008). To gain insight into

the mechanism by which NOX is activated in cells treated with TYMS-directed drugs, we

examined expression of mRNAs encoding several NOX subunits, including catalytic (NOX1-4

and p22phox) as well as regulatory (p47phox, p67phox, p40phox, NOX01, NOXA1, and Rac1).

For most mRNAs, there were no detectable changes in levels of mRNA expression following Downloaded from

exposure to FdUrd, as measured by qPCR (data not shown). The exception was the NOX2

regulatory subunit p67phox, which is required for maximal activity of the NOX2 isoform molpharm.aspetjournals.org (Italiano et al., 2012). Expression of p67phox mRNA was up-regulated ~20-25-fold by FdUrd (p

= 5.1 x 10-5) (Fig. 5A). This up-regulation was prevented by addition of dThd (p = 5.0 x 10-6),

and was significantly attenuated in TYMS-overproducing HCT116/200 cells (p = 2.0 x 10-5)

(Fig. 5A). Thus, TYMS inhibition and subsequent reduction of dTMP pool levels are crucial to at ASPET Journals on October 2, 2021

the up-regulation of p67phox.

Interestingly, the antioxidant NAC, as well as NOX inhibitors DPI and VAS, reduced the

drug-mediated increases in p67phox mRNA (p = 1.3 x 10-3 for NAC, 8.0 x 10-5 for DPI, and 9.0

x 10-4 for VAS) (Fig. 5B). This was paralleled by reduced levels of p67phox protein (Fig. 5C).

These observations suggest a “feed-forward” mechanism whereby ROS generated by NOX

activation leads to induction of p67phox and NOX activity.

The observation of induced p67phox expression in response to TYMS inhibitors, coupled

with the fact that p67phox specifically regulates the NOX2 isoform (Block and Gorin, 2012;

Jiang et al., 2011; Sumimoto, 2008), implies the latter as significant in activation of NOX

activity and subsequent apoptosis accompanying drug exposure. Therefore, we assessed the

impact of NOX2 down-regulation using siRNA transfection. Introduction of NOX2-specific

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siRNAs led to ~50% reduction in NOX2 mRNA in both control and FdUrd-treated cells (p = 1.5 x 10-3 and 2 x 10-2, respectively), while a control non-specific “scrambled” siRNA had no effect

(Fig. 6A). Reduction of NOX2 expression had essentially no impact on basal NOX activity levels prior to drug exposure (Fig. 6B), indicating that the isoform contributes little to NOX activity in normal cells. In contrast, the NOX2-specific siRNA completely inhibited the FdUrd-

mediated increase in enzyme activity (p = 0.011) (Fig. 6B), signifying that this increase is largely Downloaded from due to NOX2. A modest, yet significant, ~30% reduction in the apoptotic index was observed in

FdUrd-treated cells transfected with the NOX2-specific siRNA (p = 0.013), while there was molpharm.aspetjournals.org measurable effect of the siRNA in untreated cells (Fig. 6C). Thus, associated with down- regulation of NOX2 mRNA expression was attenuation of drug-mediated induction of both NOX activity and apoptotic cell death, implying that the NOX2 isoform plays a significant role in the

apoptotic response to TYMS inhibitors. at ASPET Journals on October 2, 2021

Alterations in the redox transcriptome by TYMS inhibitors. In light of the results reported in the previous sections, we were interested in determining the impact of TYMS-

directed antimetabolites on the cellular transcriptome, particularly with regard to mRNAs

involved in redox metabolism. We therefore carried out a whole genome cDNA microarray analysis of HCT116 cells both prior to and following a 24 h exposure to 10 µM FUra. Data were filtered to include transcripts exhibiting at least a 1.5-fold change with a p-value <0.005. We

found 1,975 genes whose levels of expression were altered by FUra; among these, 1,119 (56.6%)

were induced in response to drug, while 856 (43.4%) were repressed (Supplemental Table 1).

For the induced genes, 452 (41%) increased by 2-fold or more, 63 (5.6%) by 4-fold or more, and

16 (1.4%) by 6-fold or more; the largest induction was observed for CEACAM1, which

increased by ~14-fold. Among the repressed genes, 243 (28%) decreased by 2-fold or more, 12

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(1.4%) by 4-fold or more, and 4 (0.5%) by 6-fold or more; the largest change was exhibited by

HIST1H2BF, which decreased by ~8-fold.

To identify redox-related transcripts (the redox transcriptome), we queried both the GO

(Gene Ontogeny) and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases using the

terms "dehydro, dehydrog, hydro, hydrog, oxid, oxidase, oxidation, redox, reduc, reductase".

Those present in the microarray were considered FUra-regulated redox genes. This strategy led Downloaded from to identification of 54 genes, 27 of which were up-regulated following drug exposure (e.g.,

AKR1B10, ALDH3A1, FDXR, GGT1, GPX1, GLRX2, SAT1, SOD2, HMOX1, LOXL4, molpharm.aspetjournals.org CBR3), and 27 that were down-regulated (e.g., DHRS2, CYB5RL, HSD17B8, ACADSB,

CRYL1, SORD) (Supplemental Table 2). The presence of FDXR among the up-regulated genes

corroborates earlier findings by others (Hwang et al., 2001; Liu and Chen, 2002). p67phox did

not show up in the microarray, likely due to its low levels of expression. Our findings, overall, at ASPET Journals on October 2, 2021

indicate that exposure to TYMS inhibitors modifies the redox transcriptome within the cell

through altered expression of a variety of redox-related genes.

NRF2-regulated genes are among those induced by TYMS inhibitors. Notably,

several of the redox transcripts whose expression is modulated by FUra (e.g., AKR1B10,

ALDH3A1, GGT1, HMOX1) are known to be regulated by transcription factor NRF2. NRF2 is

a member of the cap ‘n collar family of transcription factors that controls expression of genes

conferring protection against oxidative and electrophilic stress (Baird and Dinkova-Kostova,

2011; Jaramillo and Zhang, 2013). Table 2 lists 27 transcripts from the microarray whose

expression levels have been identified in the literature as regulated by NRF2 (Agyeman et al.,

2012; Choi et al., 2014; Hayes and Dinkova-Kostova, 2014; Suzuki et al., 2013). We tested 15

of these by qPCR, and confirmed all as inducible by FdUrd (Table 2). An additional six

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transcripts, representing known NRF2-regulated genes that did not appear in the microarray,

were examined by qPCR, and shown to be induced by FdUrd (Table 3). In all, we identified 33

NRF2-modulated genes whose levels of expression change in response to TYMS inhibitors.

We determined the extent to which these findings apply to additional colon tumor cell

lines. Fig. 7A-D shows the results of qPCR analysis of mRNA levels for four genes (AKR1B10,

ALDH3A1, HSPB8, and SERPINE1) in cell lines SW480 and HCT-15, as compared to Downloaded from

HCT116. Though considerable heterogeneity in expression of these genes was observed among

the three cell lines, induction of expression by FdUrd was observed in all three, though to molpharm.aspetjournals.org variable extents. It is thus apparent that increased expression of NRF2-regulated genes in the presence of TYMS inhibitors is not specific to cell line HCT116, but occurs among distinct colon tumor cell lines.

To verify that these genes are indeed NRF2-regulated, we examined their expression at ASPET Journals on October 2, 2021 following siRNA-mediated down-regulation of the transcription factor in HCT116 cells. As shown in Fig. 7E, we observed a 40-60% reduction in mRNA levels for AKR1B10 (p = 0.017),

ALDH3A1 (p = 0.016), HSPB8 (p = 0.043), and SERPINE1 (p = 0.019) following introduction of an NRF2-specific siRNA.

Nuclear accumulation of NRF2 and its role in apoptotic response to TYMS inhibitors. Under normal circumstances, NRF2 is maintained at low levels within the cell, a status maintained by the transcription factor’s intrinsically short half-life. NRF2 is degraded by ubiquitin-mediated proteasomal degradation facilitated by the adaptor molecule Kelch-like ECH- associated protein 1 (KEAP1) (Baird and Dinkova-Kostova, 2011; Geismann et al., 2014;

Jaramillo and Zhang, 2013; Kansanen et al., 2013; Ma and He, 2012). Under conditions of oxidative or electrophilic stress, KEAP1 becomes disabled, allowing NRF2 to escape

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degradation and accumulate in the nucleus, where it binds antioxidant response elements (AREs) within promoter regions and induces transcription (Baird and Dinkova-Kostova, 2011; Jaramillo and Zhang, 2013). To determine the concentration and intracellular locale of NRF2 both prior to and following exposure to TYMS inhibitors, we carried out Western immunoblotting of cytoplasmic and nuclear fractions of HCT116 cells. Fig. 8A shows that NRF2 was present in the

nucleus, with little, if any, in the . Furthermore, its concentration in the nucleus Downloaded from increases following treatment with FdUrd.

The finding that induction of NRF2-regulated genes by TYMS inhibitors is associated molpharm.aspetjournals.org with an increase in the nuclear NRF2 concentration prompted us to ask if such induction impacts apoptosis in FdUrd-treated cells. Therefore, we analyzed apoptotic indices in cells in which

NRF2 levels were down-regulated by siRNAs (see Fig. 7E, above). For this analysis, we

reduced the FdUrd concentrations to 10 µM, in order to maximize the chances of observing an at ASPET Journals on October 2, 2021 increase in apoptosis following reduction of NRF2 concentrations; this resulted in slightly lower extents of apoptosis as compared to experiments in Figs. 2, 4, and 6, above. As shown in Fig.

8B, the apoptotic index increased by ~80% in FdUrd-treated HCT116 cells transfected with

NRF2-specific siRNAs, as compared to cells with a control siRNA (p = 0.017). We also examined TYMS-overproducing HCT116/200 cells, which are relatively resistant to TYMS inhibitors (see Fig. 1) (Berger et al., 1988). These cells, as expected, exhibited a reduced apoptotic index relative to parental HCT116 cells; similar to the parental cells, there was a 70% increase in apoptosis following exposure to FdUrd (p = 0.024). Thus, down-regulation of NRF2 levels results in sensitization to drug exposure.

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Discussion

ROS are well-known mediators of both tumorigenesis as well as response to cytotoxic agents (Gupta et al., 2012; Nogueira and Hay, 2013; Ozben, 2007; Trachootham et al., 2009).

They are generally maintained at higher concentrations in tumor cells relative to normal cells, and can function as pro-tumorigenic signaling molecules that promote cell growth and

proliferation. However, due to their highly reactive nature, ROS levels that are excessive can Downloaded from lead to intracellular molecular damage that includes chemical modification of macromolecules and small metabolites, oxidative stress, and cell death. Thus, cancer cells must maintain levels molpharm.aspetjournals.org of ROS that are high enough to sustain robust cell growth, yet below the threshold that initiates intracellular oxidative damage. This requires an intricate balance between pro- and anti- oxidants. Augmented ROS levels in tumor cells puts them closer to this threshold, making them

vulnerable to excessive oxidative stress. This creates an opportunity to augment the efficacy of at ASPET Journals on October 2, 2021 therapeutic agents used in the control of cancer (Trachootham et al., 2009). Indeed, it is likely that modification of the intracellular redox environment in the direction of excess ROS will enhance the sensitivity of tumors to cytotoxic drugs used in cancer .

In the current study, we have examined the role of oxidative stress in the cytotoxic effects of TYMS-targeted antimetabolites. We have shown that ROS levels are increased following exposure to TYMS inhibitors such as FUra, FdUrd, and RTX (Fig. 1). Such increases are attenuated by the antioxidant NAC, by dThd, and by overproduction of TYMS. Thus, it is

TYMS inhibition, as opposed to some other effect of drug, that underlies stimulation of ROS levels. Drug-mediated apoptotic cell death, like ROS levels, is reduced by NAC, indicating that

ROS induction is critical to promotion of apoptosis (Fig. 2). These observations, in total, strongly suggest that oxidative stress plays a central role in cell death mediated by TYMS-

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MOL #99614

targeted agents. It is evident that TYMS inhibitors stimulate increases in ROS concentrations

that exceed the threshold required for initiation of oxidative stress, and eventual cell death.

We have identified NADPH oxidase (NOX) as a source of increased ROS levels in cells

responding to TYMS inhibitors. NOX occurs as a family of at least seven multi-subunit

●- complexes that catalyze transfer of an electron from NADPH to O2, generating O2 (Block and

Gorin, 2012; Brandes et al., 2014; Jiang et al., 2011; Sumimoto, 2008). Activities of NOX Downloaded from

complexes respond to a wide range of hormonal, chemical, viral, and bacterial stimuli, and have

been implicated in a variety of physiological functions, including host defense, cell signaling, molpharm.aspetjournals.org and the regulation of gene expression (Block and Gorin, 2012; Jiang et al., 2011; Sumimoto,

2008). Several findings described in the present report support the notion that NOX contributes

to oxidative stress and apoptotic cell death brought on by exposure to TYMS inhibitors. First,

total NOX enzyme activity was significantly increased in the presence of drug (Fig. 3A). at ASPET Journals on October 2, 2021

Second, three NOX inhibitors (DPI, APO, and VAS) markedly attenuated increases in both ROS

levels (Fig. 3B) and apoptotic indices (Fig. 4) in response to TYMS inhibitors. Third, expression of p67phox, a regulatory subunit for the NOX2 isoform, was up-regulated in cells exposed to

TYMS inhibitors (Fig. 5). Finally, introduction of a NOX2-specific siRNA into cells completely abrogated increases in NOX activity, and resulted in attenuation of apoptosis following drug treatment (Fig. 6). These findings, collectively, indicate that NOX, in particular the NOX2 isoform, is a source of increased ROS in response to TYMS-directed agents.

Interestingly, drug-induced NOX enzyme activity was completely inhibited by the

NOX2-specific siRNA (Fig. 6B), while apoptosis was reduced by only ~30% (Fig. 6C). This suggests that increased NOX2 activity does not fully account for the apoptotic response to drug exposure. Other NOX isoforms may be involved, a notion that will require further investigation.

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Other enzymes of redox metabolism that are induced or activated by TYMS inhibitors (e.g.,

FDXR) may also be important. This possibility is consistent with analysis of the effects of FUra on the cellular transcriptome, in which mRNAs corresponding to a number of dehydrogenases, reductases, and oxidases were impacted (Supplemental Table 2). Thus, TYMS-targeted antimetabolites elicit marked modifications in the redox transcriptome, which may determine the

oxidative environment within the cell, and as a consequence, the cytotoxic impact of drug Downloaded from exposure.

Of note is the observation that several transcripts induced by TYMS inhibitors are known molpharm.aspetjournals.org target genes of transcription factor NRF2, which plays a central role in ameliorating oxidative and electrophilic stress within cells. Genes regulated by NRF2 exert their protective effects in a variety of ways, including export of xenobiotic compounds, reduction in ROS levels, and

removal or metabolism of oxidative by-products (Baird and Dinkova-Kostova, 2011; Hayes and at ASPET Journals on October 2, 2021

Dinkova-Kostova, 2014; Jaramillo and Zhang, 2013). NRF2 is normally maintained at low levels within the cell due to its high rate of proteasomal degradation, which is mediated by the factor’s binding to Kelch-like ECH-associated protein 1 (KEAP1) (Baird and Dinkova-Kostova,

2011; Geismann et al., 2014; Jaramillo and Zhang, 2013; Kansanen et al., 2013; Ma and He,

2012). During oxidative or electrophilic stress, KEAP1 is inactivated, resulting in stabilization and accumulation of NRF2, eventually leading to induction of ARE-containing genes (Baird and

Dinkova-Kostova, 2011; Jaramillo and Zhang, 2013). Consistent with this model of NRF2 activation, we find that exposure to FdUrd leads to an accumulation of the transcription factor in the nucleus (Fig. 8), providing a mechanism by which TYMS-directed antimetabolites activate

NRF2-regulated transcription. Furthermore, we found that siRNA-mediated down-regulation of

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NRF2 leads to increased apoptosis in FdUrd-treated cells, indicating that the transcription factor

inhibits apoptotic response to TYMS inhibitors, and generates a chemoresistant state.

Analysis of several colon tumor cell lines showed that while considerable heterogeneity in expression of the NRF2-regulated genes exists, induction of expression by FdUrd was observed in all three, though to variable extents (Fig. 7). This heterogeneity among cell lines is

not unexpected. It should be recalled that the cDNA microarray experiment leading to the Downloaded from identification of these genes was carried out in HCT116 cells; it is therefore feasible that an overlapping, yet distinct, set of drug-inducible genes exist in the other cells lines, and would molpharm.aspetjournals.org have been recognized had the microarray analyses been carried out in those lines.

In a number of circumstances, NRF2 has been shown to confer relative resistance to

chemotherapeutic agents (Kensler et al., 2007; Ma and He, 2012; Wang et al., 2008). Such may

be the case for TYMS inhibitors. Our observations invite speculation that expression of NRF2- at ASPET Journals on October 2, 2021

regulated genes, and their induction by TYMS inhibitors, may constrain therapeutic response to

this class of drugs. Further studies will be necessary to determine which of the many NRF2-

modulated genes mediate reduced drug response. Furthermore, the cDNA microarray analysis

presented in the current report makes it clear that many genes that are not regulated by NRF2 are

induced by exposure to TYMS inhibitors, and could be involved in drug response. Thus, it is

likely that NRF2 is one of many molecular players that control cellular response to TYMS

inhibitors.

In conclusion, the current study shows that TYMS-targeted antimetabolites induce

oxidative stress that promotes cell death; at the same time, these agents activate antioxidative

mechanisms that inhibit or reverse such stress and constrain drug response. Thus, the relative

balance between these two processes determines the cytotoxic impact of drug exposure. This has

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MOL #99614

important implications to the clinical use of TYMS inhibitors in cancer treatment. By reducing

NRF2 levels within the cell, and preventing the nuclear accumulation of the transcription factor that occurs in the presence of TYMS inhibitors, it may be possible to increase the efficacy of these drugs, thereby enhancing their clinical impact. With this in mind, ongoing efforts are aimed at a deeper understanding of the role of NRF2 as a determinant of response to TYMS-

directed antimetabolites. Downloaded from

molpharm.aspetjournals.org at ASPET Journals on October 2, 2021

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Acknowledgments

We thank Dr. Diego Altomare of the South Carolina College of Pharmacy, DNA Microarray

Core Facility, for assistance with microarrays and data analysis.

Participated in research design: Ozer, Barbour, Clinton, Berger

Conducted experiments: Ozer, Barbour, Clinton Downloaded from

Contributed new reagents or analytic tools:

Performed data analysis: Ozer, Barbour, Clinton, Berger molpharm.aspetjournals.org Wrote or contributed to the writing of the manuscript: Ozer, Barbour, Berger

at ASPET Journals on October 2, 2021

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Footnotes

This work was supported by the National Cancer Institute [Grant CA44013]; and the Centers of

Biomedical Research Excellence program of the National Institute of General Medical Sciences

[Grant GM103336]. The Microarray Core Facility receives partial support from South Carolina

IDeA Networks of Biomedical Research Excellence [Grant P20GM103499].

Downloaded from

Address correspondence to: Dr. Franklin G. Berger, Center for Colon Cancer Research, molpharm.aspetjournals.org University of South Carolina, Columbia, SC 29208. TEL: 803-777-1231; FAX: 803-777-1173;

EMAIL: [email protected]

at ASPET Journals on October 2, 2021

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Figure Legends

Fig. 1. Exposure to TYMS inhibitors leads to increased ROS levels. (A) HCT116 cells were

treated for 24 h in the indicated concentrations of FdUrd and incubated with DCFDA; ROS

levels were assessed by flow cytometry. (B-D) Cells were treated for 24 h with TYMS

inhibitors (10 µM FUra, 10 µM FdUrd, or 1 µM RTX), either alone (B), or in the presence of 10 Downloaded from

mM NAC (C) or 10 µM dThd (D). Following addition of DCFDA, ROS levels were measured

by fluorescence microscopy (upper panel) or flow cytometry (lower panel). (E) TYMS- molpharm.aspetjournals.org overproducing, FdUrd-overproducing HCT116/200 cells were treated for 24 h with drugs (10

µM FUra, 10 µM FdUrd, or 1 µM RTX), and ROS levels were analyzed by fluorescence

microscopy (upper panel) or flow cytometry (lower panel). (F) ROS levels in cell lines HCT-15

(left panel) and SW480 (right panel) were analyzed by flow cytometry following treatment with at ASPET Journals on October 2, 2021

10 µM FdUrd for 24 h. Control, untreated cells are indicated by CONT.

Fig. 2. Induction of ROS by TYMS inhibitors promotes apoptosis. Apoptotic indices in

HCT116 cells in response to 48 h treatment with TYMS inhibitors (10 µM FUra, 100 µM FdUrd, or 1 µM RTX), either alone or in the presence of 10 mM NAC, were measured by TUNEL assays; apoptotic indices were expressed relative to untreated cells.

Fig. 3. Role of NOX in ROS induction by TYMS inhibitors. (A) Total NOX activities were measured in HCT116 cells following 24 h exposure to TYMS inhibitors (10 µM FUra or 10 µM

FdUrd), either alone or in the presence of 10 µM DPI or 10 µM dThd. HCT116/200 cells were analyzed following exposure to TYMS inhibitors alone. Activities were normalized to those in

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control, untreated cells. (B) HCT116 cells were exposed to TYMS inhibitors (10 µM FUra, 10

µM FdUrd, or 1 µM RTX) either alone, or in the presence of 10 µM DPI, 1 µM APO, or 10 µM

VAS. Cells were stained with DCFDA, and observed by fluorescence microscopy.

Fig. 4. Role of NOX in apoptotic response to TYMS inhibitors. HCT116 cells were exposed for

48 h to TYMS inhibitors (10 µM FUra, 100 µM FdUrd, or 1 µM RTX), either alone or in the Downloaded from

presence of 10 µM DPI, 1 µM APO, or 10 µM VAS. Apoptotic indices were measured by

TUNEL assays. molpharm.aspetjournals.org

Fig. 5. Induction of p67phox mRNA by TYMS inhibitors. (A) HCT116 cells were treated for

24 h with 10 µM FdUrd, either alone or in the presence of 10 µM dThd. RNA was extracted and

analyzed for p67phox mRNA levels by qPCR. HCT116/200 cells were analyzed following at ASPET Journals on October 2, 2021

exposure to FdUrd alone. The induction of p67phox mRNA concentrations relative to that in

untreated cells is shown. (B) HCT116 cells were treated for 24 h with 10 µM FdUrd either alone

or in the presence of 10 µM NAC, 10 µM DPI, or 10 µM VAS, and p67phox mRNA levels were

analyzed by qPCR. Induction of p67phox mRNA concentrations relative to that in untreated

cells is shown.

Fig. 6. Down-regulation of the NOX2 isoform attenuates response to TYMS inhibitors. (A)

HCT116 cells were transfected for 24 h with a scrambled, non-specific control siRNA or a

NOX2-specific siRNA, and exposed to 10 µM FdUrd for an additional 24 h. NOX2 mRNA

levels were analyzed by qPCR. (B) Cells transfected for 24 h with a scrambled, non-specific

control siRNA or a NOX2-specific siRNA were exposed to 10 µM FdUrd for an additional 24 h,

33

Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version.

MOL #99614

and assayed for total NOX enzyme activities. (C) Cells transfected for 24 h with a scrambled,

non-specific control siRNA or a NOX2-specific siRNA were exposed to 100 µM FdUrd for an additional 48 h, and the apoptotic index was measured by TUNEL assays.

Fig. 7. NRF2-regulated genes are induced by TYMS inhibitors. HCT116, SW480, and HCT-15

cells were treated for 24 h with 10 µM FdUrd, and expression of mRNAs corresponding to Downloaded from several NRF2 target genes were analyzed by qPCR, including: (A) AKR1B10; (B) ALDH3A1;

(C) HSPB8; and (D) SERPINE1. For each mRNA, values were expressed relative to those in molpharm.aspetjournals.org untreated HCT116 cells. (E) HCT116 cells were transfected for 24 h with a scrambled, non- specific control siRNA or the NRF2-specific siRNAs; expression of the indicated mRNAs, as well as NRF2 (inset), was analyzed by qPCR.

at ASPET Journals on October 2, 2021

Fig. 8. (A) Cytoplasmic (Cyto) and nuclear (Nuc) extracts were prepared from control HCT116 cells and from those treated for 24 h with FdUrd. NRF2 levels were assessed by Western blotting. LDH and Lamin were measured to assure separation of cytoplasmic and nuclear fractions, respectively. (B) Cells (HCT116 and TYMS-overproducing HCT116/200) were transfected for 24 h with a scrambled, non-specific control siRNA or NRF2-specific siRNAs, and treated for an additional 48 h with 10 µM FdUrd. Apoptotic indices were measured by

TUNEL assays.

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Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version.

MOL #99614

TABLE 1 Sequences of the primers for quantitative RT-PCR

Genes Primers (5’ to 3’)

AKR1B10 sense: 5’- ACCTGTTCATCGTCAGCAAG -3’

antisense: 5’- CATCCCCAGACTTGAATCCC -3’ Downloaded from ALDH3A1 sense: 5’- TGCTACGTGGACAAGAACTG -3’

antisense: 5’- CACAATTTGGTTCTGGATCGAG -3’ molpharm.aspetjournals.org

GAPDH sense: 5’- TCCCTGAGCTGAACGGGAAG -3’

antisense: 5’- GGAGGAGTGGGTGTCGCTGT -3’

HSPB8 sense: 5’- AAAGATGGATACGTGGAGGTG -3’ at ASPET Journals on October 2, 2021

antisense: 5’- GGGAAAGTGAGGCAAATACTG -3’

NOX2 sense: 5’- GCCCAAAGGTGTCCAAGCT -3’

antisense: 5’- TCCCCAACGATGCGGATAT -3’ p67phox sense: 5’- ACCAGAAGCATTAACCGAGAC -3’

antisense: 5’- TTCCCTCGAAGCTGAATCAAG -3’

SERPINE1 sense: 5’- GTGGACTTTTCAGAGGTGGAG -3’

antisense: 5’- GAAGTAGAGGGCATTCACCAG 3’

35

Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version.

MOL #99614

TABLE 2

Identification of FUra-inducible NRF2 target genes by gene expression profiling

NRF2 target genes identified in the whole genome microarray analysis (Supplemental Table S2) are listed. Classification of each gene as an NRF2 target is based upon the literature (24-27) .

The fold change represents the extent of induction by exposure to 10 µM FUra for 24 h (see Downloaded from text). The p-value is corrected for multiple testing using the Benjamini-Hochberg algorithm

(see Materials and Methods). Targets in boldface were tested by qPCR, and confirmed as molpharm.aspetjournals.org inducible by FdUrd.

Gene Description Fold change Corrected

p-value at ASPET Journals on October 2, 2021

ABCC2 ATP-binding cassette, sub-family C, member 2 1.5861826 0.000741887

AGPAT9 Acylglycerol-3-phosphate O-acyltransferase 9 1.6375676 0.000784155

AHR Aryl hydrocarbon receptor 1.742765 0.001298002

AKR1B10 Aldo-keto reductase family 1, member B10 6.701502 2.20317E-05

AKR1B15 Aldo-keto reductase family 1, member B15 6.0408144 0.000258688

AKR1C1 Aldo-keto reductase family 1, member C1 2.3066108 0.001858692

AKR1C3 Aldo-keto reductase family 1, member C3 1.9071698 0.001267411

ALDH3A1 Aldehyde dehydrogenase family 3, member A1 2.0209148 0.001248846

ALDH4A1 Aldehyde dehydrogenase family 4, member A1 2.560456 0.000557924

ATF3 Activating transcription factor 3 3.492217 6.41362E-05

BLVRB Biliverdin reductase B 2.0149345 0.001494992

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Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version.

MOL #99614

GADD45A Growth arrest and DNA-damage-inducible, alpha 2.0611608 0.000269189

GBE1 Glucan (1,4-alpha-), branching enzyme 1 1.7280452 6.94566E-05

GGT1 Gamma-glutamyltransferase 1 2.475309 0.000289259

GLRX2 Glutaredoxin 2 1.6844928 0.000622618

GLS 2.4446886 0.000183834

HMOX1 Heme oxygenase 1 2.0041764 1.4295E-05 Downloaded from

HSPB8 Heat shock 22 kDa protein 8 2.7588468 0.00043559

KIFAP3 Kinesin-associated protein 3 1.807134 0.00020369

LIPH , member H 1.9393841 0.000126275 molpharm.aspetjournals.org

MAFF v-maf avian musculoaponeurotic fibrosarcoma 2.1331222 8.87782E-05

oncogene homolog F

MGST3 Microsomal glutathione S- 3 1.5016723 0.0031992

MT1B Metallothionein 1B 1.5310463 0.000482686 at ASPET Journals on October 2, 2021

MT2A Metallothionein 2A 1.7345982 0.002288793

SAT1 Spermidine/spermine N1-acetyltransferase 1 2.4873772 6.04632E-05

SERPINE1 Serpin peptidase inhibitor, clade E, member 1 5.988837 7.4388E-05

SPP1 Secreted phosphoprotein 1 3.0035641 5.6968E-05

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Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version.

MOL #99614

TABLE 3

Additional NRF2 target genes induced by TYMS inhibitors, identified by qPCR

Genes that did not show up in the microarray analysis, but are known from the literature to be

NRF2 targets (24-27), were tested for response to TYMS inhibitors by qPCR. The fold-change

represents the extent of induction by 10 µM FdUrd (with 10 µM folinic acid) for 24 h prior to Downloaded from harvesting.

molpharm.aspetjournals.org Gene Description Fold change

ABCC5 ATP-binding cassette, sub-family C, member 5 2.1 ± 0.1

AOX1 Aldehyde oxidase 1 2.2 ± 0.5

CES1 Carboxylesterase 1 4.9 ± 2.4 at ASPET Journals on October 2, 2021

GSTA1 Glutathione S-transferase alpha 1 7.6 ± 2.4

GSTM1 Glutathione S-transferase mu 1 5.2 ± 0.2

GSTM4 Glutathione S-transferase mu 4 2.8 ± 0.5

38

Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 2, 2021 Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 2, 2021 Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 2, 2021 Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 2, 2021 Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 2, 2021 Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 2, 2021 Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 2, 2021 Molecular Pharmacology Fast Forward. Published on October 6, 2015 as DOI: 10.1124/mol.115.099614 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 2, 2021 Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites Ufuk Ozer, Karen W. Barbour, Sarah A. Clinton, and Franklin G. Berger MOLECULAR PHARMACOLOGY

Supplemental Table 1. FUra-responsive genes as determined by cDNA microarray analysis

The fold change represents the extent of induction by exposure to 10 µM FUra for 24 h (see text). The p-value is corrected for multiple testing using the Benjamini-Hochberg algorithm (see Materials and Methods).

Fold Corrected Gene Symbol Description Regulation p-value Change p-value ABCA12 ATP-binding cassette, sub-family A (ABC1), member 12 3.98 up 0.000047 0.0000005 ABCB9 ATP-binding cassette, sub-family B (MDR/TAP), member 9 2.58 up 0.003948 0.0008169 ABCC2 ATP-binding cassette, sub-family C (CFTR/MRP), member 2 1.59 up 0.000742 0.0000717 ABHD4 abhydrolase domain containing 4 2.02 up 0.000102 0.0000023 ABHD8 abhydrolase domain containing 8 2.80 up 0.000030 0.0000002 ABTB2 repeat and BTB (POZ) domain containing 2 1.52 up 0.002639 0.0004639 ACRC acidic repeat containing 1.68 up 0.004630 0.0010282 ACSS2 acyl-CoA synthetase short-chain family member 2 1.60 up 0.001742 0.0002599 ACTA2 , alpha 2, smooth muscle, aorta 2.41 up 0.000263 0.0000128 ACVRL1 activin A receptor type II-like 1 2.60 up 0.003060 0.0005714 ACYP1 acylphosphatase 1, erythrocyte (common) type 1.58 up 0.003952 0.0008184 ADIRF adipogenesis regulatory factor 1.56 up 0.004089 0.0008590 ADRB2 adrenoceptor beta 2, surface 3.42 up 0.000061 0.0000008 AEN apoptosis enhancing 1.68 up 0.000288 0.0000151 AGPAT4 1-acylglycerol-3-phosphate O-acyltransferase 4 2.69 up 0.000898 0.0000964 AGPAT9 1-acylglycerol-3-phosphate O-acyltransferase 9 1.64 up 0.000784 0.0000784 AHR aryl hydrocarbon receptor 1.74 up 0.001298 0.0001688 AIM1L absent in melanoma 1-like 1.81 up 0.000164 0.0000053 AJUBA ajuba LIM protein 1.69 up 0.004296 0.0009259 AK1 adenylate 1 1.95 up 0.000130 0.0000036 AKR1B10 aldo-keto reductase family 1, member B10 (aldose reductase) 6.70 up 0.000022 0.0000001 AKR1B15 aldo-keto reductase family 1, member B15 6.04 up 0.000259 0.0000125 AKR1C1 aldo-keto reductase family 1, member C1 2.31 up 0.001859 0.0002856 AKR1C3 aldo-keto reductase family 1, member C3 1.91 up 0.001267 0.0001628 ALCAM activated leukocyte cell adhesion molecule 1.57 up 0.001951 0.0003055 ALDH3A1 aldehyde dehydrogenase 3 family, member A1 2.02 up 0.001249 0.0001590 ALDH4A1 aldehyde dehydrogenase 4 family, member A1 2.56 up 0.000558 0.0000465 ALOX12P2 arachidonate 12-lipoxygenase 2 2.01 up 0.002014 0.0003187 ALOX5 arachidonate 5-lipoxygenase 1.69 up 0.000454 0.0000323 AMDHD1 domain containing 1 1.56 up 0.002121 0.0003416 AMOTL2 angiomotin like 2 1.97 up 0.000103 0.0000023 AMZ2 archaelysin family metallopeptidase 2 1.73 up 0.001129 0.0001367 AMZ2P1 archaelysin family metallopeptidase 2 pseudogene 1 1.64 up 0.000160 0.0000051 ANAPC13 anaphase promoting complex subunit 13 1.54 up 0.004966 0.0011319 ANGPTL4 angiopoietin-like 4 3.54 up 0.000034 0.0000002 ANKEF1 ankyrin repeat and EF-hand domain containing 1 1.93 up 0.000126 0.0000034 ANKRA2 ankyrin repeat, family A (RFXANK-like), 2 2.10 up 0.000064 0.0000010 ANKRD10 ankyrin repeat domain 10 1.77 up 0.000311 0.0000173 ANKRD19P ankyrin repeat domain 19, pseudogene 1.56 up 0.001527 0.0002147 ANKRD2 ankyrin repeat domain 2 (stretch responsive muscle) 2.73 up 0.001254 0.0001600 ANKRD20A12P ankyrin repeat domain 20 family, member A12, pseudogene 4.55 up 0.000283 0.0000147 ANKRD29 ankyrin repeat domain 29 1.56 up 0.000882 0.0000940 ANTXR2 anthrax toxin receptor 2 1.73 up 0.000210 0.0000085 ANXA8L1 annexin A8-like 1 2.51 up 0.000280 0.0000143 ANXA9 annexin A9 1.73 up 0.000297 0.0000160 AP1S2 adaptor-related protein complex 1, sigma 2 subunit 1.57 up 0.001594 0.0002275 APLP1 amyloid beta (A4) precursor-like protein 1 2.04 up 0.001394 0.0001872 apolipoprotein B mRNA editing enzyme, catalytic polypeptide- APOBEC3B 1.81 up 0.000017 0.0000000 like 3B apolipoprotein B mRNA editing enzyme, catalytic polypeptide- APOBEC3C 1.82 up 0.000147 0.0000045 like 3C apolipoprotein B mRNA editing enzyme, catalytic polypeptide- APOBEC3F 1.98 up 0.000850 0.0000882 like 3F apolipoprotein B mRNA editing enzyme, catalytic polypeptide- APOBEC3H 3.32 up 0.000301 0.0000164 like 3H APOE apolipoprotein E 1.71 up 0.000704 0.0000658 AQP3 aquaporin 3 (Gill blood group) 3.35 up 0.000020 0.0000000 ARC activity-regulated cytoskeleton-associated protein 1.96 up 0.000364 0.0000224 AREG amphiregulin 1.60 up 0.001699 0.0002498 ARG2 2 3.23 up 0.000206 0.0000082 ARHGAP27 Rho GTPase activating protein 27 2.85 up 0.000468 0.0000342 ARHGEF5 Rho guanine exchange factor (GEF) 5 1.53 up 0.000965 0.0001085 ARMCX3 armadillo repeat containing, X-linked 3 1.73 up 0.002856 0.0005193 ARMCX6 armadillo repeat containing, X-linked 6 1.63 up 0.000709 0.0000664 ARRDC4 arrestin domain containing 4 1.55 up 0.000389 0.0000249 ARTN artemin 1.79 up 0.000509 0.0000400 ARVCF armadillo repeat gene deleted in velocardiofacial syndrome 1.69 up 0.002541 0.0004387 ASGR1 asialoglycoprotein receptor 1 2.62 up 0.000133 0.0000038 ASTN2 astrotactin 2 2.12 up 0.000716 0.0000677 ATF3 activating transcription factor 3 3.49 up 0.000064 0.0000010 ATG16L2 autophagy related 16-like 2 (S. cerevisiae) 1.66 up 0.001483 0.0002051 ATG4A autophagy related 4A, cysteine peptidase 1.60 up 0.002062 0.0003287 ATL1 atlastin GTPase 1 1.52 up 0.001534 0.0002163 ATP2C2 ATPase, Ca++ transporting, type 2C, member 2 1.58 up 0.003256 0.0006264 ATP6V0A4 ATPase, H+ transporting, lysosomal V0 subunit a4 7.10 up 0.000436 0.0000299 ATP6V0E2 ATPase, H+ transporting V0 subunit e2 2.36 up 0.000041 0.0000003 ATP6V0E2-AS1 ATP6V0E2 antisense RNA 1 1.55 up 0.003532 0.0006997 ATP6V1D ATPase, H+ transporting, lysosomal 34kDa, V1 subunit D 2.04 up 0.000063 0.0000009 ATP6V1F ATPase, H+ transporting, lysosomal 14kDa, V1 subunit F 1.52 up 0.000538 0.0000437 ATXN7L1 ataxin 7-like 1 2.27 up 0.003392 0.0006624 AVPI1 vasopressin-induced 1 2.97 up 0.000102 0.0000022 BAD BCL2-associated agonist of cell death 1.57 up 0.000184 0.0000066 BAI2 brain-specific angiogenesis inhibitor 2 1.84 up 0.000100 0.0000021 BATF2 basic leucine zipper transcription factor, ATF-like 2 2.18 up 0.000278 0.0000141 BAX BCL2-associated X protein 1.68 up 0.000599 0.0000517 BBC3 BCL2 binding component 3 2.59 up 0.000091 0.0000017 BCAR3 breast cancer anti-estrogen resistance 3 1.92 up 0.000208 0.0000083 BCL6 B-cell CLL/lymphoma 6 1.90 up 0.000459 0.0000331 BEST4 bestrophin 4 2.88 up 0.002364 0.0003952 BHLHE40 basic helix-loop-helix family, member e40 1.83 up 0.000202 0.0000078 BIRC2 baculoviral IAP repeat containing 2 1.54 up 0.000630 0.0000559 BIRC3 baculoviral IAP repeat containing 3 2.97 up 0.000061 0.0000009 BLCAP bladder cancer associated protein 1.62 up 0.000563 0.0000471 BLOC1S2 biogenesis of lysosomal organelles complex-1, subunit 2 1.82 up 0.000120 0.0000031 BLOC1S3 biogenesis of lysosomal organelles complex-1, subunit 3 1.50 up 0.003397 0.0006635 biogenesis of lysosomal organelles complex-1, subunit 5, BLOC1S5 1.57 up 0.002550 0.0004413 muted BLVRB biliverdin reductase B (flavin reductase (NADPH)) 2.01 up 0.001495 0.0002076 BMS1 BMS1 ribosome biogenesis factor 1.57 up 0.000047 0.0000005 BNIP3L BCL2/adenovirus E1B 19kDa interacting protein 3-like 1.89 up 0.004644 0.0010317 BTBD10 BTB (POZ) domain containing 10 2.23 up 0.000082 0.0000015 BTBD11 BTB (POZ) domain containing 11 1.64 up 0.000318 0.0000179 BTG1 B-cell translocation gene 1, anti-proliferative 2.04 up 0.000108 0.0000025 BTG2 BTG family, member 2 3.06 up 0.000100 0.0000020 BTG3 BTG family, member 3 1.51 up 0.000896 0.0000961 BTN2A2 butyrophilin, subfamily 2, member A2 1.63 up 0.001378 0.0001840 C10orf12 10 open reading frame 12 2.20 up 0.000243 0.0000109 C10orf54 open reading frame 54 2.10 up 0.000044 0.0000004 C11orf52 open reading frame 52 1.90 up 0.000850 0.0000883 C11orf86 chromosome 11 open reading frame 86 4.44 up 0.002107 0.0003387 C12orf4 open reading frame 4 1.66 up 0.001001 0.0001147 C12orf5 chromosome 12 open reading frame 5 1.59 up 0.002273 0.0003737 C17orf89 chromosome 17 open reading frame 89 1.67 up 0.004967 0.0011336 C19orf57 open reading frame 57 2.34 up 0.000044 0.0000004 C1orf106 open reading frame 106 2.90 up 0.000027 0.0000001 C1orf116 chromosome 1 open reading frame 116 3.99 up 0.000090 0.0000017 C1orf54 chromosome 1 open reading frame 54 2.43 up 0.000159 0.0000051 C1QTNF6 C1q and tumor necrosis factor related protein 6 1.55 up 0.000140 0.0000042 C1S complement component 1, s subcomponent 2.26 up 0.000431 0.0000293 C21orf91 chromosome 21 open reading frame 91 1.78 up 0.000400 0.0000260 C2CD2L C2CD2-like 1.75 up 0.004510 0.0009903 C2orf43 open reading frame 43 1.55 up 0.000079 0.0000014 C4orf47 chromosome 4 open reading frame 47 1.57 up 0.002746 0.0004895 C5orf42 chromosome 5 open reading frame 42 1.83 up 0.004916 0.0011151 C6orf226 chromosome 6 open reading frame 226 1.90 up 0.000253 0.0000119 C8orf44 chromosome 8 open reading frame 44 2.02 up 0.000043 0.0000004 CA2 II 2.49 up 0.000167 0.0000056 calcium channel, voltage-dependent, P/Q type, alpha 1A CACNA1A 1.74 up 0.000487 0.0000368 subunit CALB2 calbindin 2 1.69 up 0.000477 0.0000350 CALCOCO2 calcium binding and coiled-coil domain 2 1.51 up 0.000119 0.0000030 CALHM3 calcium homeostasis modulator 3 2.41 up 0.000939 0.0001039 CAMK2B calcium/calmodulin-dependent II beta 4.60 up 0.002364 0.0003954 CAPG capping protein (actin filament), -like 1.62 up 0.001668 0.0002438 CAPN13 calpain 13 1.58 up 0.000915 0.0000992 CARHSP1 calcium regulated heat stable protein 1, 24kDa 1.52 up 0.000947 0.0001051 CASP10 caspase 10, apoptosis-related cysteine peptidase 1.69 up 0.003055 0.0005695 CASP4 caspase 4, apoptosis-related cysteine peptidase 1.92 up 0.000039 0.0000003 CASP5 caspase 5, apoptosis-related cysteine peptidase 2.11 up 0.000497 0.0000382 CAST calpastatin 1.68 up 0.000029 0.0000002 CATSPER1 cation channel, sperm associated 1 1.97 up 0.001743 0.0002601 CBR3 carbonyl reductase 3 1.89 up 0.003410 0.0006666 CBS cystathionine-beta-synthase 3.30 up 0.000200 0.0000077 CCDC90B coiled-coil domain containing 90B 1.50 up 0.000250 0.0000116 CCDC96 coiled-coil domain containing 96 1.62 up 0.000102 0.0000022 CCL26 chemokine (C-C motif) ligand 26 4.94 up 0.000241 0.0000107 CCL3 chemokine (C-C motif) ligand 3 2.00 up 0.001067 0.0001258 CCND3 cyclin D3 2.23 up 0.000014 0.0000000 CCNE1 cyclin E1 1.69 up 0.001508 0.0002109 CCNE2 cyclin E2 3.06 up 0.001859 0.0002858 CCNG2 cyclin G2 2.17 up 0.004254 0.0009118 CCRL2 chemokine (C-C motif) receptor-like 2 5.08 up 0.000053 0.0000006 CD274 CD274 molecule 2.86 up 0.000116 0.0000029 CD33 CD33 molecule 1.51 up 0.000590 0.0000507 CD47 CD47 molecule 1.62 up 0.000124 0.0000033 CD55 molecule, decay accelerating factor for complement CD55 1.88 up 0.000253 0.0000118 (Cromer blood group) CD68 CD68 molecule 2.27 up 0.000029 0.0000002 CD79B CD79b molecule, immunoglobulin-associated beta 5.64 up 0.003888 0.0007965 CD82 CD82 molecule 3.54 up 0.000038 0.0000003 CD83 CD83 molecule 1.85 up 0.000495 0.0000380 CDA 1.93 up 0.000022 0.0000001 CDC42BPG CDC42 binding protein kinase gamma (DMPK-like) 2.12 up 0.002425 0.0004099 CDCA5 cell division cycle associated 5 1.52 up 0.000271 0.0000135 CDCP1 CUB domain containing protein 1 1.82 up 0.000044 0.0000004 CDH1 cadherin 1, type 1, E-cadherin (epithelial) 1.54 up 0.001195 0.0001480 CDIP1 cell death-inducing p53 target 1 2.60 up 0.001805 0.0002737 CDK2 cyclin-dependent kinase 2 1.55 up 0.000389 0.0000249 CDKN1A cyclin-dependent kinase inhibitor 1A (p21, Cip1) 3.83 up 0.000056 0.0000007 CDKN1C cyclin-dependent kinase inhibitor 1C (p57, Kip2) 2.13 up 0.000054 0.0000006 CDKN2C cyclin-dependent kinase inhibitor 2C (p18, inhibits CDK4) 1.70 up 0.000106 0.0000025 CDKN2D cyclin-dependent kinase inhibitor 2D (p19, inhibits CDK4) 1.68 up 0.001232 0.0001554 carcinoembryonic antigen-related cell adhesion molecule 1 CEACAM1 13.86 up 0.000056 0.0000007 (biliary glycoprotein) CENPP protein P 1.73 up 0.000938 0.0001037 CENPQ centromere protein Q 1.87 up 0.000102 0.0000022 CENPU centromere protein U 1.51 up 0.000614 0.0000536 CERS6 ceramide synthase 6 1.56 up 0.002558 0.0004432 CGB chorionic gonadotropin, beta polypeptide 2.16 up 0.000509 0.0000400 CGRRF1 cell growth regulator with ring finger domain 1 1.69 up 0.003010 0.0005581 CHIC2 cysteine-rich hydrophobic domain 2 1.97 up 0.000164 0.0000054 CHM choroideremia (Rab escort protein 1) 2.61 up 0.003329 0.0006472 CHMP1B charged multivesicular body protein 1B 1.56 up 0.000850 0.0000883 CHRD chordin 1.81 up 0.000742 0.0000718 CHRNA7 (cholinergic receptor, nicotinic, alpha 7, 5-10) CHRFAM7A and FAM7A (family with sequence similarity 7A, exons A-E) 2.54 up 0.004040 0.0008458 fusion CHRNA7 cholinergic receptor, nicotinic, alpha 7 (neuronal) 2.42 up 0.000074 0.0000012 CHRNB1 cholinergic receptor, nicotinic, beta 1 (muscle) 2.07 up 0.000278 0.0000141 CHST12 carbohydrate (chondroitin 4) sulfotransferase 12 1.52 up 0.001761 0.0002639 CHST6 carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 6 1.90 up 0.000098 0.0000020 CHST7 carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 7 1.59 up 0.001570 0.0002225 Cbp/p300-interacting transactivator, with Glu/Asp-rich CITED4 1.70 up 0.000060 0.0000008 carboxy-terminal domain, 4 CLDN4 claudin 4 1.72 up 0.000551 0.0000456 CLEC16A C-type lectin domain family 16, member A 2.71 up 0.002145 0.0003466 CLIC3 chloride intracellular channel 3 1.52 up 0.002290 0.0003775 CLIC4 chloride intracellular channel 4 1.66 up 0.000127 0.0000035 CLIC5 chloride intracellular channel 5 3.33 up 0.001130 0.0001370 CLK4 CDC-like kinase 4 1.53 up 0.002288 0.0003769 CLPB ClpB caseinolytic peptidase B homolog (E. coli) 1.58 up 0.000560 0.0000467 CMTM3 CKLF-like MARVEL transmembrane domain containing 3 1.72 up 0.000191 0.0000071 CNN1 calponin 1, basic, smooth muscle 6.13 up 0.000034 0.0000002 CNOT1 CCR4-NOT transcription complex, subunit 1 1.54 up 0.001336 0.0001755 CNST consortin, connexin sorting protein 1.57 up 0.000037 0.0000002 COBLL1 cordon-bleu WH2 repeat protein-like 1 1.84 up 0.000289 0.0000152 COL16A1 collagen, type XVI, alpha 1 2.18 up 0.001235 0.0001559 COL4A6 collagen, type IV, alpha 6 1.55 up 0.000598 0.0000516 COL9A3 collagen, type IX, alpha 3 1.75 up 0.000442 0.0000307 COQ10B coenzyme Q10 homolog B (S. cerevisiae) 1.52 up 0.000159 0.0000050 CORO2A coronin, actin binding protein, 2A 1.71 up 0.004989 0.0011407 CORO6 coronin 6 1.95 up 0.000528 0.0000423 CPE carboxypeptidase E 2.00 up 0.000022 0.0000001 CPNE8 copine VIII 1.58 up 0.001505 0.0002102 CREB3 cAMP responsive element binding protein 3 1.91 up 0.001237 0.0001565 CREB3L3 cAMP responsive element binding protein 3-like 3 1.88 up 0.000754 0.0000737 CRELD2 cysteine-rich with EGF-like domains 2 1.62 up 0.000347 0.0000209 CRIP1 cysteine-rich protein 1 (intestinal) 1.79 up 0.000163 0.0000053 CRIP2 cysteine-rich protein 2 2.08 up 0.000170 0.0000058 CRIPT cysteine-rich PDZ-binding protein 1.60 up 0.000416 0.0000277 CRISPLD2 cysteine-rich secretory protein LCCL domain containing 2 2.35 up 0.000063 0.0000009 CRLF1 cytokine receptor-like factor 1 1.65 up 0.001293 0.0001675 CSF1R colony stimulating factor 1 receptor 2.04 up 0.000416 0.0000276 CSF2 colony stimulating factor 2 (granulocyte-macrophage) 5.56 up 0.001739 0.0002587 CSGALNACT2 chondroitin sulfate N-acetylgalactosaminyltransferase 2 2.27 up 0.004438 0.0009687 CSRNP1 cysteine-serine-rich nuclear protein 1 2.88 up 0.000046 0.0000005 CST6 cystatin E/M 2.11 up 0.000040 0.0000003 CSTF3 cleavage stimulation factor, 3' pre-RNA, subunit 3, 77kDa 1.59 up 0.000209 0.0000085 CTGF connective tissue growth factor 2.96 up 0.001055 0.0001237 CTSD cathepsin D 1.65 up 0.000247 0.0000113 CTSK cathepsin K 1.72 up 0.001399 0.0001889 CTSV cathepsin V 1.86 up 0.001646 0.0002379 CUL4B cullin 4B 1.61 up 0.000046 0.0000005 CXCL16 chemokine (C-X-C motif) ligand 16 1.54 up 0.002189 0.0003560 CXCR4 chemokine (C-X-C motif) receptor 4 3.98 up 0.000039 0.0000003 CXorf40B chromosome X open reading frame 40B 1.60 up 0.000329 0.0000191 CXorf57 chromosome X open reading frame 57 1.61 up 0.000226 0.0000096 CYB5R1 cytochrome b5 reductase 1 1.66 up 0.002679 0.0004731 CYFIP2 cytoplasmic FMR1 interacting protein 2 2.03 up 0.001676 0.0002454 CYHR1 cysteine/histidine-rich 1 1.79 up 0.000197 0.0000075 CYP2S1 cytochrome P450, family 2, subfamily S, polypeptide 1 1.69 up 0.000834 0.0000850 CYP4F11 cytochrome P450, family 4, subfamily F, polypeptide 11 2.16 up 0.000444 0.0000310 CYP4F12 cytochrome P450, family 4, subfamily F, polypeptide 12 2.56 up 0.001262 0.0001615 CYR61 cysteine-rich, angiogenic inducer, 61 3.68 up 0.000109 0.0000026 CYSRT1 cysteine-rich tail protein 1 3.33 up 0.000029 0.0000002 CYSTM1 cysteine-rich transmembrane module containing 1 1.63 up 0.000441 0.0000305 CYTH4 cytohesin 4 3.28 up 0.000086 0.0000016 DACT3 dishevelled-binding antagonist of beta-catenin 3 2.10 up 0.000168 0.0000057 DAPP1 dual adaptor of phosphotyrosine and 3-phosphoinositides 8.72 up 0.000054 0.0000007 DBR1 debranching RNA lariats 1 1.51 up 0.000206 0.0000082 DDB2 damage-specific DNA binding protein 2, 48kDa 2.67 up 0.000311 0.0000173 DDIAS DNA damage-induced apoptosis suppressor 1.69 up 0.000525 0.0000419 DDIT3 DNA-damage-inducible transcript 3 1.71 up 0.001292 0.0001674 DEF8 differentially expressed in FDCP 8 homolog (mouse) 1.77 up 0.001046 0.0001220 DENND2A DENN/MADD domain containing 2A 2.36 up 0.000879 0.0000934 DENND2C DENN/MADD domain containing 2C 1.79 up 0.000235 0.0000103 DENND3 DENN/MADD domain containing 3 1.52 up 0.000621 0.0000546 DES 1.53 up 0.001073 0.0001270 DGKA , alpha 80kDa 2.56 up 0.000501 0.0000387 DHRS11 dehydrogenase/reductase (SDR family) member 11 1.77 up 0.003168 0.0006002 DHRS13 dehydrogenase/reductase (SDR family) member 13 1.87 up 0.001244 0.0001581 DHRS7 dehydrogenase/reductase (SDR family) member 7 1.59 up 0.000098 0.0000020 DISP1 dispatched homolog 1 (Drosophila) 2.19 up 0.000713 0.0000672 DISP2 dispatched homolog 2 (Drosophila) 2.23 up 0.000054 0.0000006 DKK1 dickkopf WNT signaling pathway inhibitor 1 1.63 up 0.001371 0.0001826 DLK2 delta-like 2 homolog (Drosophila) 1.73 up 0.000446 0.0000312 DLX2 distal-less homeobox 2 1.73 up 0.000539 0.0000439 DLX4 distal-less homeobox 4 2.00 up 0.000839 0.0000859 DMPK dystrophia myotonica-protein kinase 1.66 up 0.003888 0.0007962 DMTF1 cyclin D binding myb-like transcription factor 1 1.50 up 0.003532 0.0006999 DNAJB5 DnaJ (Hsp40) homolog, subfamily B, member 5 1.59 up 0.002145 0.0003468 DNAJC1 DnaJ (Hsp40) homolog, subfamily C, member 1 1.62 up 0.000958 0.0001072 DNAJC18 DnaJ (Hsp40) homolog, subfamily C, member 18 2.00 up 0.001904 0.0002956 DOK7 docking protein 7 3.99 up 0.000551 0.0000456 DPF1 D4, zinc and double PHD fingers family 1 1.64 up 0.000269 0.0000133 DPYSL4 -like 4 2.66 up 0.000103 0.0000023 DRAM1 DNA-damage regulated autophagy modulator 1 2.35 up 0.000290 0.0000153 DRAXIN dorsal inhibitory axon guidance protein 3.45 up 0.000646 0.0000583 DRICH1 aspartate-rich 1 1.52 up 0.003831 0.0007793 DSG2 desmoglein 2 1.57 up 0.000503 0.0000391 DUSP1 dual specificity 1 1.54 up 0.000243 0.0000109 DUSP13 dual specificity phosphatase 13 2.17 up 0.000132 0.0000037 DUSP14 dual specificity phosphatase 14 2.42 up 0.000133 0.0000038 DUSP4 dual specificity phosphatase 4 1.74 up 0.000074 0.0000012 DUSP5 dual specificity phosphatase 5 2.40 up 0.000020 0.0000000 dual-specificity -(Y)- regulated kinase DYRK3 1.62 up 0.000342 0.0000204 3 E2F7 E2F transcription factor 7 2.24 up 0.000264 0.0000129 EBI3 Epstein-Barr virus induced 3 4.18 up 0.000089 0.0000017 ECM1 extracellular matrix protein 1 4.17 up 0.000047 0.0000005 EDN2 endothelin 2 12.48 up 0.000253 0.0000119 EDRF1 erythroid differentiation regulatory factor 1 1.95 up 0.003508 0.0006915 EFEMP2 EGF containing fibulin-like extracellular matrix protein 2 1.89 up 0.003199 0.0006098 EFNB1 ephrin-B1 1.96 up 0.000858 0.0000897 EFR3B EFR3 homolog B (S. cerevisiae) 2.19 up 0.000528 0.0000423 EGR2 early growth response 2 3.68 up 0.000477 0.0000353 EGR4 early growth response 4 2.00 up 0.003663 0.0007348 EHD2 EH-domain containing 2 1.50 up 0.000713 0.0000671 E74-like factor 3 (ets domain transcription factor, epithelial- ELF3 1.87 up 0.000541 0.0000442 specific ) ELK3 ELK3, ETS-domain protein (SRF accessory protein 2) 2.29 up 0.000684 0.0000633 EMC7 ER membrane protein complex subunit 7 1.62 up 0.001693 0.0002487 EMX1 empty spiracles homeobox 1 1.53 up 0.001410 0.0001913 ENHO energy homeostasis associated 1.89 up 0.000343 0.0000204 ENPP4 ectonucleotide pyrophosphatase/ 4 (putative) 1.57 up 0.003085 0.0005780 ENSA endosulfine alpha 1.79 up 0.000672 0.0000617 EPAS1 endothelial PAS domain protein 1 1.97 up 0.000040 0.0000003 EPHA2 EPH receptor A2 2.36 up 0.000338 0.0000200 EPHB3 EPH receptor B3 2.11 up 0.001199 0.0001492 EPPK1 epiplakin 1 2.54 up 0.000135 0.0000039 EPS8L1 EPS8-like 1 1.54 up 0.001897 0.0002941 EPS8L2 EPS8-like 2 2.23 up 0.000446 0.0000312 ERAP2 endoplasmic reticulum aminopeptidase 2 2.24 up 0.000492 0.0000375 v-erb-b2 avian erythroblastic leukemia viral oncogene homolog ERBB3 1.76 up 0.000283 0.0000147 3 ERICH2 glutamate-rich 2 3.26 up 0.000047 0.0000005 ERMP1 endoplasmic reticulum metallopeptidase 1 1.58 up 0.001242 0.0001575 ESAM endothelial cell adhesion molecule 2.08 up 0.000152 0.0000048 ESPNL -like 2.60 up 0.000165 0.0000054 ETNK2 ethanolamine kinase 2 1.59 up 0.001500 0.0002089 EXO1 1 1.74 up 0.000180 0.0000064 EXT1 exostosin glycosyltransferase 1 1.66 up 0.002299 0.0003801 F3 coagulation factor III (thromboplastin, tissue factor) 1.76 up 0.000127 0.0000035 FA2H fatty acid 2-hydroxylase 2.07 up 0.000102 0.0000021 FAAH2 fatty acid amide 2 1.54 up 0.000400 0.0000260 FAAHP1 fatty acid amide hydrolase pseudogene 1 3.88 up 0.000047 0.0000005 FAM105A family with sequence similarity 105, member A 1.77 up 0.000745 0.0000725 FAM110C family with sequence similarity 110, member C 2.40 up 0.000027 0.0000001 FAM111A family with sequence similarity 111, member A 2.34 up 0.000441 0.0000305 FAM122B family with sequence similarity 122B 1.65 up 0.002226 0.0003640 FAM126A family with sequence similarity 126, member A 2.31 up 0.003928 0.0008107 FAM129A family with sequence similarity 129, member A 2.49 up 0.000095 0.0000019 FAM174A family with sequence similarity 174, member A 1.58 up 0.003252 0.0006231 FAM189A2 family with sequence similarity 189, member A2 2.83 up 0.000481 0.0000358 FAM199X family with sequence similarity 199, X-linked 1.61 up 0.000150 0.0000046 FAM210B family with sequence similarity 210, member B 2.03 up 0.000205 0.0000081 FAM212B family with sequence similarity 212, member B 3.34 up 0.000079 0.0000014 FAM214A family with sequence similarity 214, member A 2.70 up 0.000040 0.0000003 FAM214B family with sequence similarity 214, member B 1.72 up 0.002834 0.0005132 FAM25A family with sequence similarity 25, member A 3.01 up 0.000024 0.0000001 FAM27C family with sequence similarity 27, member C 1.86 up 0.000482 0.0000360 FAM46B family with sequence similarity 46, member B 2.96 up 0.000548 0.0000452 FAM46C family with sequence similarity 46, member C 1.64 up 0.004263 0.0009148 FAM71E1 family with sequence similarity 71, member E1 1.52 up 0.000903 0.0000972 FAM83E family with sequence similarity 83, member E 2.56 up 0.000217 0.0000089 FAM84B family with sequence similarity 84, member B 1.73 up 0.000335 0.0000197 FAM8A1 family with sequence similarity 8, member A1 1.70 up 0.000104 0.0000024 FAM92B family with sequence similarity 92, member B 5.84 up 0.000112 0.0000027 FAM98C family with sequence similarity 98, member C 1.57 up 0.000806 0.0000813 FANCB Fanconi anemia, complementation group B 1.62 up 0.001659 0.0002413 FAS Fas cell surface death receptor 3.97 up 0.000215 0.0000088 FBLIM1 filamin binding LIM protein 1 3.98 up 0.003145 0.0005935 FBLN1 fibulin 1 1.89 up 0.000114 0.0000028 FBLN5 fibulin 5 2.10 up 0.001682 0.0002464 FBXO2 F-box protein 2 1.63 up 0.000631 0.0000560 FBXO22 F-box protein 22 1.53 up 0.001651 0.0002391 FDXR ferredoxin reductase 2.27 up 0.000178 0.0000063 FER1L4 fer-1-like 4 (C. elegans), pseudogene 2.29 up 0.000926 0.0001014 FGD6 FYVE, RhoGEF and PH domain containing 6 2.28 up 0.000227 0.0000097 FGFR1OP FGFR1 oncogene partner 1.51 up 0.002066 0.0003303 FHL2 four and a half LIM domains 2 2.80 up 0.000035 0.0000002 FICD FIC domain containing 1.55 up 0.000684 0.0000633 c-fos induced growth factor (vascular endothelial growth factor FIGF 1.93 up 0.001513 0.0002119 D) FLNC filamin C, gamma 1.76 up 0.001098 0.0001310 FLT3LG fms-related 3 ligand 1.96 up 0.000750 0.0000731 FOLR1 folate receptor 1 (adult) 1.75 up 0.000548 0.0000451 FOSL1 FOS-like antigen 1 1.65 up 0.000083 0.0000015 FOSL2 FOS-like antigen 2 1.92 up 0.000350 0.0000212 FOXA1 forkhead box A1 1.76 up 0.000108 0.0000025 FOXD1 forkhead box D1 1.64 up 0.000742 0.0000716 FOXP1 forkhead box P1 2.39 up 0.000402 0.0000263 FOXQ1 forkhead box Q1 2.19 up 0.003296 0.0006373 FRS2 fibroblast growth factor receptor substrate 2 1.58 up 0.003260 0.0006275 FRZB frizzled-related protein 2.55 up 0.000566 0.0000475 FST follistatin 4.02 up 0.000102 0.0000022 fucosyltransferase 3 (galactoside 3(4)-L-fucosyltransferase, FUT3 3.30 up 0.000042 0.0000004 Lewis blood group) FXYD3 FXYD domain containing ion transport regulator 3 5.10 up 0.000052 0.0000006 FXYD6 FXYD domain containing ion transport regulator 6 1.78 up 0.003533 0.0007013 GABARAP GABA(A) receptor-associated protein 1.53 up 0.003009 0.0005578 GABARAPL1 GABA(A) receptor-associated protein like 1 1.68 up 0.002189 0.0003560 GAD1 glutamate decarboxylase 1 (brain, 67kDa) 1.84 up 0.000501 0.0000388 GADD45A growth arrest and DNA-damage-inducible, alpha 2.06 up 0.000269 0.0000134 GALNT5 polypeptide N-acetylgalactosaminyltransferase 5 2.96 up 0.000039 0.0000003 GAST gastrin 4.28 up 0.000102 0.0000021 GATA2 GATA binding protein 2 1.82 up 0.000431 0.0000293 GBE1 glucan (1,4-alpha-), branching enzyme 1 1.73 up 0.000069 0.0000011 GBX2 gastrulation brain homeobox 2 2.31 up 0.000544 0.0000445 GCH1 GTP cyclohydrolase 1 2.28 up 0.000051 0.0000006 GCHFR GTP cyclohydrolase I feedback regulator 2.12 up 0.000253 0.0000118 GDA 1.68 up 0.000184 0.0000066 GDAP2 ganglioside induced differentiation associated protein 2 1.63 up 0.000127 0.0000035 GDI1 GDP dissociation inhibitor 1 1.60 up 0.003122 0.0005880 GEM GTP binding protein overexpressed in 1.66 up 0.000740 0.0000712 GFI1 growth factor independent 1 transcription repressor 1.73 up 0.000093 0.0000018 GFOD1 glucose-fructose domain containing 1 1.72 up 0.002689 0.0004757 GGCT gamma-glutamylcyclotransferase 1.56 up 0.002013 0.0003183 GGT1 gamma-glutamyltransferase 1 2.48 up 0.000289 0.0000152 GGT3P gamma-glutamyltransferase 3 pseudogene 2.12 up 0.000312 0.0000174 GGTLC1 gamma-glutamyltransferase light chain 1 3.12 up 0.000040 0.0000003 GGTLC2 gamma-glutamyltransferase light chain 2 2.59 up 0.000254 0.0000121 GJB4 gap junction protein, beta 4, 30.3kDa 3.65 up 0.000022 0.0000001 GJB5 gap junction protein, beta 5, 31.1kDa 2.70 up 0.000061 0.0000008 GLRX glutaredoxin (thioltransferase) 1.54 up 0.000476 0.0000349 GLRX2 glutaredoxin 2 1.68 up 0.000623 0.0000547 GLS glutaminase 2.44 up 0.000184 0.0000067 GLTP glycolipid transfer protein 1.58 up 0.001780 0.0002681 GM2A GM2 ganglioside activator 1.88 up 0.000990 0.0001128 GNAS GNAS complex 1.52 up 0.000206 0.0000082 guanine nucleotide binding protein (G protein), gamma GNGT1 2.34 up 0.000074 0.0000012 transducing activity polypeptide 1 GP1BB glycoprotein Ib (platelet), beta polypeptide 1.87 up 0.000462 0.0000335 GPATCH11 G patch domain containing 11 1.52 up 0.000576 0.0000487 GPM6A glycoprotein M6A 1.68 up 0.003010 0.0005585 GPR124 G protein-coupled receptor 124 1.58 up 0.002998 0.0005553 GPR137 G protein-coupled receptor 137 1.58 up 0.002380 0.0003986 GPR162 G protein-coupled receptor 162 1.97 up 0.002007 0.0003170 GPR35 G protein-coupled receptor 35 2.27 up 0.001805 0.0002731 GPR56 G protein-coupled receptor 56 2.30 up 0.000068 0.0000010 GPR87 G protein-coupled receptor 87 4.47 up 0.000014 0.0000000 GPRC5A G protein-coupled receptor, class C, group 5, member A 2.17 up 0.000294 0.0000157 GPX1 glutathione peroxidase 1 1.65 up 0.000812 0.0000823 GRAMD1B GRAM domain containing 1B 2.57 up 0.002219 0.0003622 GRAMD3 GRAM domain containing 3 1.69 up 0.001630 0.0002351 GRB7 growth factor receptor-bound protein 7 2.22 up 0.000147 0.0000045 GREB1 growth regulation by estrogen in breast cancer 1 1.72 up 0.003173 0.0006018 GRIN2C glutamate receptor, ionotropic, N-methyl D-aspartate 2C 1.81 up 0.004894 0.0011073 GSE1 Gse1 coiled-coil protein 1.74 up 0.004492 0.0009849 GSN gelsolin 1.76 up 0.000836 0.0000853 GSTT2 glutathione S-transferase theta 2 1.82 up 0.001871 0.0002886 GSTT2B glutathione S-transferase theta 2B (gene/pseudogene) 1.91 up 0.000103 0.0000023 H19, imprinted maternally expressed transcript (non-protein H19 3.04 up 0.000116 0.0000029 coding) HAPLN3 hyaluronan and proteoglycan link protein 3 1.79 up 0.000864 0.0000907 HAUS2 HAUS augmin-like complex, subunit 2 1.79 up 0.000477 0.0000352 HBA2 hemoglobin, alpha 2 1.92 up 0.000315 0.0000176 HBEGF heparin-binding EGF-like growth factor 3.15 up 0.000053 0.0000006 HCFC2 host cell factor C2 1.90 up 0.003302 0.0006390 HDAC11 deacetylase 11 1.75 up 0.000952 0.0001061 HDAC5 5 2.02 up 0.000073 0.0000012 HECA headcase homolog (Drosophila) 1.81 up 0.000023 0.0000001 HELZ2 helicase with zinc finger 2, transcriptional coactivator 1.67 up 0.000248 0.0000113 HERC2P2 hect domain and RLD 2 pseudogene 2 1.75 up 0.000810 0.0000819 HES2 hes family bHLH transcription factor 2 2.79 up 0.000014 0.0000000 human immunodeficiency virus type I enhancer binding protein HIVEP2 1.58 up 0.003651 0.0007312 2 HLA-A major histocompatibility complex, class I, A 1.81 up 0.001721 0.0002549 HLA-DPB1 major histocompatibility complex, class II, DP beta 1 1.60 up 0.001676 0.0002454 HLA-DQB1 major histocompatibility complex, class II, DQ beta 1 2.28 up 0.002348 0.0003909 HLA-DRB1 major histocompatibility complex, class II, DR beta 1 2.33 up 0.000014 0.0000000 HLA-DRB4 major histocompatibility complex, class II, DR beta 4 2.40 up 0.000094 0.0000018 HLA-DRB5 major histocompatibility complex, class II, DR beta 5 2.19 up 0.004900 0.0011089 HMCN2 hemicentin 2 3.16 up 0.001249 0.0001589 HMGA2 high mobility group AT-hook 2 1.83 up 0.001661 0.0002418 HMOX1 heme oxygenase (decycling) 1 2.00 up 0.000014 0.0000000 HOXB4 homeobox B4 1.79 up 0.000163 0.0000053 HOXB6 homeobox B6 1.87 up 0.001296 0.0001680 HPSE heparanase 1.56 up 0.003533 0.0007012 HRCT1 histidine rich carboxyl terminus 1 6.64 up 0.000444 0.0000309 HS1BP3 HCLS1 binding protein 3 3.13 up 0.000940 0.0001042 HS2ST1 heparan sulfate 2-O-sulfotransferase 1 1.59 up 0.002067 0.0003306 HS3ST3B1 heparan sulfate (glucosamine) 3-O-sulfotransferase 3B1 1.66 up 0.002064 0.0003294 hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid HSD3B7 1.66 up 0.000698 0.0000652 delta- 7 HSH2D hematopoietic SH2 domain containing 1.96 up 0.000763 0.0000751 HSPA4L heat shock 70kDa protein 4-like 1.65 up 0.000660 0.0000600 HSPB8 heat shock 22kDa protein 8 2.76 up 0.000436 0.0000298 HSPG2 heparan sulfate proteoglycan 2 1.93 up 0.000061 0.0000009 5-hydroxytryptamine (serotonin) receptor 1D, G protein- HTR1D 3.03 up 0.003624 0.0007246 coupled HYAL1 hyaluronoglucosaminidase 1 2.37 up 0.000102 0.0000022 inhibitor of DNA binding 3, dominant negative helix-loop-helix ID3 1.59 up 0.000127 0.0000035 protein IER3 immediate early response 3 1.81 up 0.000061 0.0000008 IER5 immediate early response 5 1.99 up 0.000116 0.0000029 IFFO1 family orphan 1 3.28 up 0.000806 0.0000814 IFI27L1 interferon, alpha-inducible protein 27-like 1 1.75 up 0.000294 0.0000157 IFI27L2 interferon, alpha-inducible protein 27-like 2 1.79 up 0.001741 0.0002594 IFI6 interferon, alpha-inducible protein 6 2.10 up 0.000135 0.0000039 IFIH1 interferon induced with helicase C domain 1 1.78 up 0.000521 0.0000415 IFIT2 interferon-induced protein with tetratricopeptide repeats 2 1.73 up 0.001111 0.0001335 IFIT3 interferon-induced protein with tetratricopeptide repeats 3 2.20 up 0.001114 0.0001340 IFITM2 interferon induced transmembrane protein 2 1.63 up 0.000448 0.0000314 IFITM3 interferon induced transmembrane protein 3 1.59 up 0.001362 0.0001808 IFNGR1 interferon gamma receptor 1 1.62 up 0.001495 0.0002075 IFRD1 interferon-related developmental regulator 1 2.48 up 0.000102 0.0000021 IGF2 insulin-like growth factor 2 (somatomedin A) 2.45 up 0.000229 0.0000100 IGFBP6 insulin-like growth factor binding protein 6 1.71 up 0.000380 0.0000239 IGFL2 IGF-like family member 2 2.63 up 0.000041 0.0000003 IKBIP IKBKB interacting protein 3.01 up 0.000441 0.0000305 IKZF5 IKAROS family zinc finger 5 (Pegasus) 1.61 up 0.004900 0.0011093 IL10RA interleukin 10 receptor, alpha 2.73 up 0.000041 0.0000003 IL10RB interleukin 10 receptor, beta 1.64 up 0.001421 0.0001935 IL11 interleukin 11 3.82 up 0.000150 0.0000047 IL17RB interleukin 17 receptor B 1.73 up 0.000033 0.0000002 IL1RAP interleukin 1 receptor accessory protein 1.83 up 0.001662 0.0002426 IL1RN interleukin 1 receptor antagonist 5.05 up 0.000006 0.0000000 IL20RB interleukin 20 receptor beta 1.99 up 0.002198 0.0003577 IL22RA1 interleukin 22 receptor, alpha 1 1.83 up 0.002572 0.0004468 IL4R interleukin 4 receptor 1.59 up 0.001378 0.0001844 IL7 interleukin 7 1.98 up 0.003285 0.0006343 ILK integrin-linked kinase 1.53 up 0.000044 0.0000004 INHBB inhibin, beta B 2.68 up 0.000638 0.0000570 INPP1 inositol polyphosphate-1-phosphatase 2.13 up 0.001705 0.0002515 INPP4A inositol polyphosphate-4-phosphatase, type I, 107kDa 1.70 up 0.001133 0.0001377 INPP5D inositol polyphosphate-5-phosphatase, 145kDa 2.58 up 0.000295 0.0000159 INTS7 integrator complex subunit 7 1.76 up 0.002062 0.0003287 IPP intracisternal A particle-promoted polypeptide 1.54 up 0.000589 0.0000505 IRF7 interferon regulatory factor 7 2.89 up 0.000106 0.0000025 IRF9 interferon regulatory factor 9 2.08 up 0.001200 0.0001494 IRS2 insulin receptor substrate 2 1.52 up 0.002055 0.0003266 IRX3 iroquois homeobox 3 1.82 up 0.002468 0.0004197 ISCU iron-sulfur cluster assembly enzyme 1.55 up 0.003901 0.0008022 ISG15 ISG15 ubiquitin-like modifier 2.46 up 0.000053 0.0000006 ISG20 interferon stimulated exonuclease gene 20kDa 2.81 up 0.000226 0.0000096 ITGA6 integrin, alpha 6 1.95 up 0.001875 0.0002895 ITGAX integrin, alpha X (complement component 3 receptor 4 subunit) 3.23 up 0.000203 0.0000079 ITGB1BP1 integrin beta 1 binding protein 1 1.55 up 0.000121 0.0000032 ITPKA inositol-trisphosphate 3-kinase A 1.79 up 0.000164 0.0000054 ITPRIP inositol 1,4,5-trisphosphate receptor interacting protein 1.71 up 0.000482 0.0000360 JAG1 jagged 1 1.88 up 0.000191 0.0000071 JUN jun proto-oncogene 2.35 up 0.001594 0.0002282 JUNB jun B proto-oncogene 1.96 up 0.000120 0.0000031 JUP junction 1.94 up 0.000060 0.0000008 KALRN kalirin, RhoGEF kinase 1.86 up 0.003827 0.0007780 KANK3 KN motif and ankyrin repeat domains 3 2.26 up 0.000217 0.0000089 KAT2B K() acetyltransferase 2B 2.60 up 0.000463 0.0000338 KATNAL1 katanin p60 subunit A-like 1 1.58 up 0.002746 0.0004897 KCNE1L KCNE1-like 4.32 up 0.000242 0.0000108 KCNK1 potassium channel, subfamily K, member 1 1.68 up 0.001102 0.0001317 KCNK6 potassium channel, subfamily K, member 6 1.57 up 0.000487 0.0000368 KCNK7 potassium channel, subfamily K, member 7 1.99 up 0.000741 0.0000714 potassium intermediate/small conductance calcium-activated KCNN4 1.60 up 0.001204 0.0001507 channel, subfamily N, member 4 KCTD21 potassium channel tetramerization domain containing 21 1.78 up 0.000621 0.0000544 KDSR 3-ketodihydrosphingosine reductase 1.72 up 0.000967 0.0001088 KIAA0040 KIAA0040 1.70 up 0.000159 0.0000050 KIAA0247 KIAA0247 2.95 up 0.000047 0.0000005 KIAA1217 KIAA1217 2.16 up 0.002558 0.0004431 KIAA1324 KIAA1324 4.86 up 0.000452 0.0000321 KIAA1683 KIAA1683 1.57 up 0.002958 0.0005429 KIAA1715 KIAA1715 1.74 up 0.004309 0.0009298 KIF16B kinesin family member 16B 2.49 up 0.000831 0.0000846 KIF1B kinesin family member 1B 1.84 up 0.001768 0.0002653 KIF3C kinesin family member 3C 1.90 up 0.003463 0.0006802 KIFAP3 kinesin-associated protein 3 1.81 up 0.000204 0.0000080 KIRREL2 kin of IRRE like 2 (Drosophila) 1.81 up 0.001395 0.0001874 KLF2 Kruppel-like factor 2 2.10 up 0.000060 0.0000008 KLHL30 kelch-like family member 30 4.31 up 0.000454 0.0000323 KLHL36 kelch-like family member 36 1.54 up 0.003669 0.0007367 KLK1 kallikrein 1 1.74 up 0.003029 0.0005635 KRT13 13 2.11 up 0.004048 0.0008482 KRT15 3.21 up 0.000054 0.0000006 KRT18 1.64 up 0.001816 0.0002764 KRT18P55 keratin 18 pseudogene 55 1.63 up 0.002241 0.0003673 KRT19P2 pseudogene 2 1.54 up 0.004377 0.0009495 KRT32 keratin 32 1.84 up 0.000249 0.0000114 KRT34 2.61 up 0.000106 0.0000024 KRT8 1.60 up 0.001055 0.0001238 KRT80 keratin 80 2.44 up 0.000633 0.0000563 KRT83 keratin 83 1.51 up 0.000416 0.0000276 KRT9 2.76 up 0.001153 0.0001410 KRTAP10-12 keratin associated protein 10-12 1.65 up 0.004741 0.0010625 KRTAP2-3 keratin associated protein 2-3 2.47 up 0.000341 0.0000202 LAGE3 L antigen family, member 3 1.51 up 0.001899 0.0002945 LAMA3 laminin, alpha 3 6.09 up 0.000014 0.0000000 LAMB2 laminin, beta 2 (laminin S) 1.67 up 0.000228 0.0000098 LAMB3 laminin, beta 3 3.65 up 0.000042 0.0000004 LAMC2 laminin, gamma 2 2.36 up 0.000090 0.0000017 LAMP2 lysosomal-associated membrane protein 2 1.52 up 0.002044 0.0003240 LAMP3 lysosomal-associated membrane protein 3 4.24 up 0.000027 0.0000001 LAT2 linker for activation of T cells family, member 2 3.81 up 0.000041 0.0000003 LATS2 large tumor suppressor kinase 2 1.82 up 0.002299 0.0003798 LCAT lecithin-cholesterol acyltransferase 1.75 up 0.002838 0.0005142 LCE1C late cornified envelope 1C 4.99 up 0.002361 0.0003945 LCE1E late cornified envelope 1E 3.03 up 0.002804 0.0005070 LCK lymphocyte-specific protein tyrosine kinase 4.76 up 0.001559 0.0002209 LETM2 leucine zipper-EF-hand containing transmembrane protein 2 2.24 up 0.000387 0.0000246 LGALS7 lectin, galactoside-binding, soluble, 7 2.50 up 0.000022 0.0000001 LGALS8 lectin, galactoside-binding, soluble, 8 1.73 up 0.002972 0.0005467 LGALS9C lectin, galactoside-binding, soluble, 9C 1.50 up 0.000492 0.0000375 LHX2 LIM homeobox 2 2.17 up 0.000031 0.0000002 LIMA1 LIM domain and actin binding 1 1.68 up 0.000765 0.0000756 LIMCH1 LIM and calponin homology domains 1 1.78 up 0.002943 0.0005393 LIMS2 LIM and senescent cell antigen-like domains 2 2.20 up 0.000528 0.0000424 LIN7A lin-7 homolog A (C. elegans) 2.30 up 0.001048 0.0001224 LINC00337 long intergenic non-protein coding RNA 337 2.30 up 0.000180 0.0000064 LINC00618 long intergenic non-protein coding RNA 618 1.61 up 0.000103 0.0000023 LINC00857 long intergenic non-protein coding RNA 857 1.66 up 0.001314 0.0001718 LINC00937 long intergenic non-protein coding RNA 937 1.92 up 0.000844 0.0000865 LINC01137 long intergenic non-protein coding RNA 1137 2.46 up 0.001668 0.0002437 LINC01270 long intergenic non-protein coding RNA 1270 1.77 up 0.000432 0.0000295 LIPH lipase, member H 1.94 up 0.000126 0.0000034 LNX1 ligand of numb-protein X 1, E3 ubiquitin protein 4.16 up 0.004724 0.0010572 LOC101928841 collagen alpha-1(II) chain-like 9.19 up 0.000124 0.0000033 LOC388242 coiled-coil domain containing 101 pseudogene 1.72 up 0.003361 0.0006546 LOC389834 ankyrin repeat domain 57 pseudogene 2.88 up 0.001264 0.0001619 LOC645166 lymphocyte-specific protein 1 pseudogene 2.34 up 0.000063 0.0000009 LOC645638 WDNM1-like pseudogene 6.39 up 0.000368 0.0000229 LOXL2 lysyl oxidase-like 2 1.59 up 0.000106 0.0000025 LOXL4 lysyl oxidase-like 4 2.04 up 0.000887 0.0000947 LRG1 leucine-rich alpha-2-glycoprotein 1 2.19 up 0.000028 0.0000001 LRP10 low density lipoprotein receptor-related protein 10 2.36 up 0.000347 0.0000208 LRRC32 leucine rich repeat containing 32 2.84 up 0.002299 0.0003798 LRRC8C leucine rich repeat containing 8 family, member C 1.51 up 0.003962 0.0008222 LSMEM1 leucine-rich single-pass membrane protein 1 3.01 up 0.000113 0.0000027 LY6D lymphocyte antigen 6 complex, locus D 2.81 up 0.000150 0.0000046 LY6G6C lymphocyte antigen 6 complex, locus G6C 2.33 up 0.001775 0.0002672 LY6K lymphocyte antigen 6 complex, locus K 1.73 up 0.000127 0.0000035 LYNX1 Ly6/neurotoxin 1 2.16 up 0.000590 0.0000506 LYPD3 LY6/PLAUR domain containing 3 2.77 up 0.002569 0.0004459 LYPD5 LY6/PLAUR domain containing 5 3.43 up 0.000041 0.0000003 LZTS1 leucine zipper, putative tumor suppressor 1 2.23 up 0.001205 0.0001508 MACC1 metastasis associated in colon cancer 1 3.83 up 0.000907 0.0000977 MAD2L2 MAD2 mitotic arrest deficient-like 2 (yeast) 4.55 up 0.003308 0.0006410 v-maf avian musculoaponeurotic fibrosarcoma oncogene MAFB 3.43 up 0.000641 0.0000576 homolog B v-maf avian musculoaponeurotic fibrosarcoma oncogene MAFF 2.13 up 0.000089 0.0000017 homolog F MAMDC4 MAM domain containing 4 1.73 up 0.001763 0.0002644 MAP1LC3B microtubule-associated protein 1 light chain 3 beta 1.91 up 0.000073 0.0000012 microtubule-associated protein 1 light chain 3 beta pseudogene MAP1LC3BP1 1.73 up 0.000380 0.0000239 1 MAP2 microtubule-associated protein 2 2.18 up 0.000043 0.0000004 MAP3K12 mitogen-activated protein kinase kinase kinase 12 2.15 up 0.000205 0.0000081 MAP3K13 mitogen-activated protein kinase kinase kinase 13 2.10 up 0.000294 0.0000157 MAP3K9 mitogen-activated protein kinase kinase kinase 9 1.64 up 0.000855 0.0000894 MAPK11 mitogen-activated protein kinase 11 1.80 up 0.003355 0.0006529 MAPK13 mitogen-activated protein kinase 13 1.79 up 0.000419 0.0000280 MAPKAP1 mitogen-activated protein kinase associated protein 1 1.70 up 0.000136 0.0000040 MAPRE2 microtubule-associated protein, RP/EB family, member 2 1.72 up 0.000135 0.0000039 MARCH9 membrane-associated ring finger (C3HC4) 9 1.57 up 0.000041 0.0000003 MARVELD3 MARVEL domain containing 3 1.53 up 0.000120 0.0000031 MASTL microtubule associated serine/threonine kinase-like 1.55 up 0.000170 0.0000058 MATN2 matrilin 2 1.85 up 0.004768 0.0010700 MBD1 methyl-CpG binding domain protein 1 1.57 up 0.000566 0.0000475 MCF2L-AS1 MCF2L antisense RNA 1 1.97 up 0.000041 0.0000003 MDK midkine (neurite growth-promoting factor 2) 1.67 up 0.000163 0.0000053 MDM2 MDM2 oncogene, E3 ubiquitin protein ligase 2.30 up 0.001836 0.0002810 MED20 mediator complex subunit 20 1.52 up 0.000858 0.0000898 MEF2BNB MEF2B neighbor 1.71 up 0.003962 0.0008220 MEIG1 /spermiogenesis associated 1 1.54 up 0.004258 0.0009130 MFGE8 milk fat globule-EGF factor 8 protein 1.80 up 0.001756 0.0002631 MFSD4 major facilitator superfamily domain containing 4 3.13 up 0.004039 0.0008449 mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N- MGAT4A 2.45 up 0.000474 0.0000348 acetylglucosaminyltransferase, isozyme A MGLL monoglyceride lipase 2.18 up 0.000228 0.0000098 MGST3 microsomal glutathione S-transferase 3 1.50 up 0.003199 0.0006100 MICALL2 MICAL-like 2 1.50 up 0.003076 0.0005754 MID2 midline 2 1.80 up 0.001396 0.0001881 MIEF2 mitochondrial elongation factor 2 1.63 up 0.000304 0.0000166 MIG7 mig-7 11.78 up 0.000291 0.0000154 MIR31HG MIR31 host gene (non-protein coding) 4.95 up 0.000204 0.0000080 MITF microphthalmia-associated transcription factor 1.75 up 0.002707 0.0004801 MKRN1 makorin ring finger protein 1 2.11 up 0.000812 0.0000823 myeloid/lymphoid or mixed-lineage leukemia (trithorax MLLT11 1.64 up 0.001480 0.0002046 homolog, Drosophila); translocated to, 11 MLXIP MLX interacting protein 1.62 up 0.003728 0.0007521 MNX1 motor neuron and pancreas homeobox 1 1.75 up 0.000686 0.0000635 MOAP1 modulator of apoptosis 1 1.55 up 0.000613 0.0000532 MORC3 MORC family CW-type zinc finger 3 1.52 up 0.000319 0.0000180 MORN4 MORN repeat containing 4 2.50 up 0.000160 0.0000051 MOSPD1 motile sperm domain containing 1 1.60 up 0.003852 0.0007864 MPC1 mitochondrial pyruvate carrier 1 1.99 up 0.000043 0.0000004 MPC2 mitochondrial pyruvate carrier 2 1.74 up 0.000028 0.0000001 MPND MPN domain containing 1.55 up 0.000598 0.0000515 MPPE1 metallophosphoesterase 1 2.36 up 0.001290 0.0001669 MPRIP phosphatase Rho interacting protein 2.98 up 0.000782 0.0000779 MPZL2 myelin protein zero-like 2 2.03 up 0.000018 0.0000000 MPZL3 myelin protein zero-like 3 1.79 up 0.000514 0.0000407 MR1 major histocompatibility complex, class I-related 2.66 up 0.000450 0.0000319 MRC2 mannose receptor, C type 2 1.77 up 0.000396 0.0000256 MROH1 maestro heat-like repeat family member 1 2.64 up 0.000266 0.0000131 MSANTD2 Myb/SANT-like DNA-binding domain containing 2 1.57 up 0.002541 0.0004390 MSI2 musashi RNA-binding protein 2 2.16 up 0.000503 0.0000391 MT1B metallothionein 1B 1.53 up 0.000483 0.0000362 MT2A metallothionein 2A 1.73 up 0.002289 0.0003772 MUC1 mucin 1, cell surface associated 1.51 up 0.000854 0.0000890 MXD1 MAX dimerization protein 1 2.27 up 0.000116 0.0000029 MYBL1 v-myb avian myeloblastosis viral oncogene homolog-like 1 2.38 up 0.000447 0.0000313 MYBPC3 myosin binding protein C, cardiac 1.59 up 0.000676 0.0000622 MYEOV myeloma overexpressed 2.16 up 0.000102 0.0000022 MYO1A myosin IA 6.52 up 0.000047 0.0000005 MYO1E myosin IE 1.95 up 0.000043 0.0000004 MYO6 myosin VI 1.65 up 0.000169 0.0000058 MYO7A myosin VIIA 2.13 up 0.000535 0.0000434 MYOM2 myomesin 2 1.77 up 0.000866 0.0000912 MYZAP myocardial zonula adherens protein 1.55 up 0.000899 0.0000966 N4BP2L2 NEDD4 binding protein 2-like 2 2.81 up 0.000098 0.0000020 NABP2 nucleic acid binding protein 2 1.55 up 0.001773 0.0002663 NAP1L5 assembly protein 1-like 5 2.20 up 0.000917 0.0000995 NAT1 N-acetyltransferase 1 (arylamine N-acetyltransferase) 1.58 up 0.002726 0.0004847 NAV3 neuron navigator 3 1.74 up 0.001924 0.0003002 NCAPH2 non-SMC condensin II complex, subunit H2 1.71 up 0.000079 0.0000013 NCEH1 neutral cholesterol ester hydrolase 1 2.39 up 0.000041 0.0000003 NCOA7 nuclear receptor coactivator 7 1.59 up 0.000135 0.0000039 NDOR1 NADPH dependent diflavin oxidoreductase 1 1.84 up 0.000445 0.0000310 NDRG1 N-myc downstream regulated 1 3.09 up 0.000014 0.0000000 NDRG4 NDRG family member 4 2.06 up 0.000097 0.0000020 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 11, NDUFB11 1.54 up 0.000022 0.0000001 17.3kDa NEK11 NIMA-related kinase 11 1.63 up 0.000958 0.0001072 NES 1.73 up 0.000875 0.0000926 NEU1 sialidase 1 (lysosomal sialidase) 2.09 up 0.000407 0.0000267 NEURL1B neuralized E3 ubiquitin protein ligase 1B 1.83 up 0.000180 0.0000064 NGEF neuronal guanine nucleotide exchange factor 1.74 up 0.000037 0.0000003 NGFR nerve growth factor receptor 2.35 up 0.000077 0.0000013 NINJ1 ninjurin 1 2.13 up 0.000204 0.0000079 NIPA1 non imprinted in Prader-Willi/Angelman syndrome 1 1.56 up 0.002996 0.0005545 NIPAL3 NIPA-like domain containing 3 2.72 up 0.000211 0.0000086 NKX3-1 NK3 homeobox 1 1.99 up 0.000082 0.0000015 NLRP1 NLR family, pyrin domain containing 1 2.81 up 0.000364 0.0000225 NMB neuromedin B 1.68 up 0.004102 0.0008645 NOL4L nucleolar protein 4-like 5.77 up 0.004789 0.0010769 NOSTRIN nitric oxide synthase trafficking 1.61 up 0.001661 0.0002419 NOTCH3 notch 3 1.86 up 0.001863 0.0002869 NOVA2 neuro-oncological ventral antigen 2 2.16 up 0.000534 0.0000432 NPNT nephronectin 1.57 up 0.001929 0.0003012 NR1D1 nuclear receptor subfamily 1, group D, member 1 1.93 up 0.000208 0.0000083 nuclear receptor subfamily 3, group C, member 1 NR3C1 1.84 up 0.000135 0.0000039 (glucocorticoid receptor) NR4A3 nuclear receptor subfamily 4, group A, member 3 2.67 up 0.002550 0.0004411 NRP1 neuropilin 1 5.17 up 0.000417 0.0000278 NT5E 5'-, ecto (CD73) 1.57 up 0.000750 0.0000730 NTN4 netrin 4 1.83 up 0.002521 0.0004335 NTPCR nucleoside-triphosphatase, cancer-related 1.72 up 0.000132 0.0000037 NUAK2 NUAK family, SNF1-like kinase, 2 2.46 up 0.000136 0.0000040 NUCB2 nucleobindin 2 1.62 up 0.000115 0.0000028 nudix (nucleoside diphosphate linked moiety X)-type motif 16- NUDT16L1 1.68 up 0.000772 0.0000764 like 1 OASL 2'-5'-oligoadenylate synthetase-like 3.55 up 0.000044 0.0000004 OCLN occludin 1.85 up 0.000537 0.0000436 ODF2 outer dense fiber of sperm tails 2 1.67 up 0.001919 0.0002985 OLFM1 olfactomedin 1 1.77 up 0.001576 0.0002235 OPTN optineurin 1.97 up 0.000301 0.0000165 ORAI3 ORAI calcium release-activated calcium modulator 3 1.62 up 0.001143 0.0001395 OSBPL2 oxysterol binding protein-like 2 1.81 up 0.000253 0.0000119 OTUD1 OTU deubiquitinase 1 1.51 up 0.002988 0.0005515 OVOL1 ovo-like zinc finger 1 1.80 up 0.000281 0.0000145 P2RY2 purinergic receptor P2Y, G-protein coupled, 2 2.20 up 0.000136 0.0000040 P4HA2 prolyl 4-hydroxylase, alpha polypeptide II 1.72 up 0.000826 0.0000840 phosphoprotein membrane anchor with glycosphingolipid PAG1 2.75 up 0.004097 0.0008619 microdomains 1 PAPD5 PAP associated domain containing 5 4.56 up 0.002172 0.0003523 PAPSS2 3'-phosphoadenosine 5'-phosphosulfate synthase 2 1.65 up 0.001399 0.0001888 PARD6A par-6 family cell polarity regulator alpha 2.40 up 0.000103 0.0000023 PARD6B par-6 family cell polarity regulator beta 1.69 up 0.000900 0.0000968 PC pyruvate carboxylase 1.52 up 0.000621 0.0000546 PCDH1 protocadherin 1 2.92 up 0.000074 0.0000012 PCGF5 polycomb group ring finger 5 1.65 up 0.002226 0.0003638 PCNA proliferating cell nuclear antigen 1.78 up 0.000136 0.0000040 PCYT1A phosphate cytidylyltransferase 1, choline, alpha 1.87 up 0.001376 0.0001837 PDE2A phosphodiesterase 2A, cGMP-stimulated 1.52 up 0.000515 0.0000408 PDE6G phosphodiesterase 6G, cGMP-specific, rod, gamma 2.85 up 0.000159 0.0000051 PDGFB platelet-derived growth factor beta polypeptide 1.50 up 0.000619 0.0000540 PDLIM3 PDZ and LIM domain 3 2.49 up 0.000028 0.0000001 PDLIM7 PDZ and LIM domain 7 (enigma) 2.38 up 0.000022 0.0000001 PDZD11 PDZ domain containing 11 1.68 up 0.000728 0.0000695 PEAR1 platelet endothelial aggregation receptor 1 2.41 up 0.000051 0.0000006 PERP PERP, TP53 apoptosis effector 1.76 up 0.000531 0.0000428 PGBD2 piggyBac transposable element derived 2 1.72 up 0.001106 0.0001322 PGF placental growth factor 2.13 up 0.000621 0.0000544 PGPEP1 pyroglutamyl-peptidase I 2.19 up 0.000206 0.0000082 PHLDA3 pleckstrin homology-like domain, family A, member 3 3.05 up 0.000115 0.0000028 PHPT1 phosphohistidine phosphatase 1 2.14 up 0.000093 0.0000018 PHYHIP phytanoyl-CoA 2-hydroxylase interacting protein 3.39 up 0.002348 0.0003910 PI4K2A phosphatidylinositol 4-kinase type 2 alpha 1.75 up 0.000016 0.0000000 PI4KB phosphatidylinositol 4-kinase, catalytic, beta 1.56 up 0.000389 0.0000249 PIDD1 p53-induced death domain protein 1 2.13 up 0.000670 0.0000615 PIM1 pim-1 oncogene 1.93 up 0.001820 0.0002772 PINK1 PTEN induced putative kinase 1 1.95 up 0.000177 0.0000062 PLA2G10 A2, group X 1.81 up 0.000673 0.0000619 PLA2G15 , group XV 1.51 up 0.000743 0.0000722 PLA2G16 phospholipase A2, group XVI 1.69 up 0.000726 0.0000692 PLA2G4D phospholipase A2, group IVD (cytosolic) 5.17 up 0.000195 0.0000074 PLAT plasminogen activator, tissue 1.74 up 0.000094 0.0000019 PLAU plasminogen activator, urokinase 4.51 up 0.000000 0.0000000 PLAUR plasminogen activator, urokinase receptor 2.17 up 0.000033 0.0000002 PLCL2 -like 2 3.38 up 0.002680 0.0004735 phosphatidylinositol-specific phospholipase C, X domain PLCXD1 1.52 up 0.002943 0.0005395 containing 1 PLEC 1.66 up 0.000894 0.0000955 pleckstrin homology domain containing, family B (evectins) PLEKHB1 1.73 up 0.001210 0.0001516 member 1 pleckstrin homology domain containing, family F (with FYVE PLEKHF1 1.74 up 0.001281 0.0001655 domain) member 1 PLIN2 perilipin 2 1.72 up 0.000663 0.0000604 PLK2 polo-like kinase 2 2.17 up 0.000054 0.0000006 PLK3 polo-like kinase 3 3.02 up 0.000163 0.0000053 PLSCR4 phospholipid scramblase 4 2.14 up 0.002517 0.0004321 PMAIP1 phorbol-12-myristate-13-acetate-induced protein 1 2.29 up 0.000166 0.0000055 PMEL premelanosome protein 2.03 up 0.002410 0.0004050 PML promyelocytic leukemia 1.59 up 0.000119 0.0000031 PNPLA8 patatin-like phospholipase domain containing 8 1.89 up 0.000577 0.0000489 PNRC1 -rich nuclear receptor coactivator 1 1.58 up 0.003049 0.0005676 POLD4 polymerase (DNA-directed), delta 4, accessory subunit 1.59 up 0.000317 0.0000178 POLH polymerase (DNA directed), eta 1.78 up 0.000219 0.0000092 PPAP2B phosphatidic type 2B 1.79 up 0.001872 0.0002889 PPL periplakin 1.66 up 0.002804 0.0005067 PPM1A , Mg2+/Mn2+ dependent, 1A 3.10 up 0.002462 0.0004178 PPM1D protein phosphatase, Mg2+/Mn2+ dependent, 1D 3.00 up 0.000020 0.0000000 PPM1K protein phosphatase, Mg2+/Mn2+ dependent, 1K 1.89 up 0.002594 0.0004523 PPM1M protein phosphatase, Mg2+/Mn2+ dependent, 1M 1.64 up 0.003280 0.0006328 PPP1R14C protein phosphatase 1, regulatory (inhibitor) subunit 14C 2.13 up 0.000183 0.0000066 PPP1R15A protein phosphatase 1, regulatory subunit 15A 1.86 up 0.000329 0.0000190 PPP2R5B , regulatory subunit B', beta 1.70 up 0.002214 0.0003609 PPT2 palmitoyl-protein 2 1.72 up 0.000548 0.0000452 PPY pancreatic polypeptide 2.07 up 0.001876 0.0002898 PRADC1 protease-associated domain containing 1 1.89 up 0.000250 0.0000116 PRDM1 PR domain containing 1, with ZNF domain 6.10 up 0.001594 0.0002282 PRH2 proline-rich protein HaeIII subfamily 2 1.67 up 0.001504 0.0002100 PRKAB1 protein kinase, AMP-activated, beta 1 non-catalytic subunit 1.93 up 0.000281 0.0000145 PRKAB2 protein kinase, AMP-activated, beta 2 non-catalytic subunit 1.76 up 0.000167 0.0000056 PRKAR1A protein kinase, cAMP-dependent, regulatory, type I, alpha 1.57 up 0.001592 0.0002269 PRKAR1B protein kinase, cAMP-dependent, regulatory, type I, beta 1.55 up 0.004157 0.0008810 PRKCH , eta 1.95 up 0.000184 0.0000067 PROCR protein C receptor, endothelial 2.34 up 0.000080 0.0000014 PRODH proline dehydrogenase (oxidase) 1 1.95 up 0.000208 0.0000084 PROM2 prominin 2 2.50 up 0.000108 0.0000025 PRR15L proline rich 15-like 2.10 up 0.000185 0.0000067 PRRG1 proline rich Gla (G-carboxyglutamic acid) 1 2.74 up 0.000091 0.0000017 PRRG2 proline rich Gla (G-carboxyglutamic acid) 2 1.79 up 0.002168 0.0003511 PRRG4 proline rich Gla (G-carboxyglutamic acid) 4 (transmembrane) 1.55 up 0.000019 0.0000000 PRSS2 protease, serine, 2 (trypsin 2) 2.27 up 0.000230 0.0000101 PRSS3 protease, serine, 3 2.11 up 0.000102 0.0000021 PRSS30P protease, serine, 30, pseudogene 1.66 up 0.000400 0.0000260 PRSS35 protease, serine, 35 5.14 up 0.003191 0.0006066 PRSS56 protease, serine, 56 3.72 up 0.000304 0.0000166 PRSS57 protease, serine, 57 2.06 up 0.002788 0.0005022 PRSS8 protease, serine, 8 1.72 up 0.000463 0.0000336 PSAPL1 prosaposin-like 1 (gene/pseudogene) 4.09 up 0.000336 0.0000198 PSMC3IP PSMC3 interacting protein 1.64 up 0.000507 0.0000397 PSORS1C1 psoriasis susceptibility 1 candidate 1 1.86 up 0.000135 0.0000039 PSTPIP2 proline-serine-threonine phosphatase interacting protein 2 1.96 up 0.000211 0.0000086 PTAFR platelet-activating factor receptor 4.27 up 0.000256 0.0000123 PTBP3 polypyrimidine tract binding protein 3 1.57 up 0.000102 0.0000022 PTPRU protein tyrosine phosphatase, receptor type, U 1.65 up 0.000250 0.0000116 PVRL1 poliovirus receptor-related 1 (herpesvirus entry mediator C) 2.92 up 0.000168 0.0000057 PVRL4 poliovirus receptor-related 4 4.45 up 0.000102 0.0000022 PXK PX domain containing serine/threonine kinase 1.75 up 0.004190 0.0008925 PYCARDOS PYCARD opposite strand 3.25 up 0.000482 0.0000361 RAB15 RAB15, member RAS oncogene family 2.02 up 0.000568 0.0000477 RAB27A RAB27A, member RAS oncogene family 2.29 up 0.000234 0.0000103 RAB3A RAB3A, member RAS oncogene family 1.73 up 0.001791 0.0002707 ras-related C3 botulinum toxin substrate 2 (rho family, small RAC2 1.92 up 0.001194 0.0001478 GTP binding protein Rac2) RAD1 RAD1 homolog (S. pombe) 1.90 up 0.000335 0.0000197 RAD51C RAD51 paralog C 1.52 up 0.000094 0.0000019 RAET1E retinoic acid early transcript 1E 2.40 up 0.001378 0.0001840 RASA4 RAS p21 protein activator 4 1.57 up 0.003892 0.0007988 RASA4B RAS p21 protein activator 4B 2.09 up 0.000563 0.0000471 RASGRP2 RAS guanyl releasing protein 2 (calcium and DAG-regulated) 2.43 up 0.000060 0.0000008 RASL10A RAS-like, family 10, member A 2.11 up 0.000227 0.0000097 RASSF5 Ras association (RalGDS/AF-6) domain family member 5 1.83 up 0.000736 0.0000705 RBM18 RNA binding motif protein 18 1.66 up 0.000917 0.0000996 RBM4B RNA binding motif protein 4B 1.53 up 0.002623 0.0004604 RBPMS2 RNA binding protein with multiple splicing 2 1.56 up 0.002064 0.0003295 RDX radixin 2.39 up 0.001553 0.0002199 RECQL5 RecQ protein-like 5 2.03 up 0.000957 0.0001070 REEP2 receptor accessory protein 2 1.98 up 0.000229 0.0000100 RELL1 RELT-like 1 1.75 up 0.000852 0.0000887 RELT RELT tumor necrosis factor receptor 1.66 up 0.001402 0.0001899 RFTN1 raftlin, lipid raft linker 1 1.96 up 0.001996 0.0003146 RFX5 regulatory factor X, 5 (influences HLA class II expression) 1.96 up 0.000102 0.0000022 RGAG4 retrotransposon gag domain containing 4 2.18 up 0.000431 0.0000292 RGCC regulator of cell cycle 1.82 up 0.000361 0.0000220 RGS20 regulator of G-protein signaling 20 1.88 up 0.000275 0.0000138 RHBDD2 rhomboid domain containing 2 1.91 up 0.001415 0.0001922 RHBDF1 rhomboid 5 homolog 1 (Drosophila) 1.57 up 0.001741 0.0002592 RHOBTB2 Rho-related BTB domain containing 2 1.55 up 0.002750 0.0004910 RHOD ras homolog family member D 2.05 up 0.000061 0.0000009 RHOF ras homolog family member F (in filopodia) 1.66 up 0.001819 0.0002771 RIMBP3 RIMS binding protein 3 2.20 up 0.001342 0.0001769 RIN1 Ras and Rab interactor 1 1.64 up 0.000770 0.0000762 RINL Ras and Rab interactor-like 2.64 up 0.000342 0.0000204 RIOK3 RIO kinase 3 2.67 up 0.000040 0.0000003 RNA component of mitochondrial RNA processing RMRP 2.50 up 0.000082 0.0000015 RNASEH2A H2, subunit A 1.62 up 0.000209 0.0000084 RND3 Rho family GTPase 3 1.79 up 0.000209 0.0000084 RNF14 ring finger protein 14 1.70 up 0.000328 0.0000188 RNF146 ring finger protein 146 1.52 up 0.000421 0.0000282 RNF182 ring finger protein 182 2.36 up 0.000191 0.0000071 RNF38 ring finger protein 38 1.52 up 0.003579 0.0007128 RNU2-1 RNA, U2 small nuclear 1 2.08 up 0.000487 0.0000368 RPL23AP7 ribosomal protein L23a pseudogene 7 1.91 up 0.000498 0.0000384 RPL27A ribosomal protein L27a 1.55 up 0.001748 0.0002612 RPS27L ribosomal protein S27-like 2.60 up 0.000279 0.0000142 RRAD Ras-related associated with diabetes 2.34 up 0.001755 0.0002628 RRAGC Ras-related GTP binding C 1.61 up 0.000949 0.0001053 RRM1 M1 1.54 up 0.000884 0.0000943 RSRP1 arginine/serine-rich protein 1 2.43 up 0.000068 0.0000010 RUFY2 RUN and FYVE domain containing 2 2.77 up 0.000907 0.0000978 RUNX1 runt-related transcription factor 1 3.60 up 0.000219 0.0000092 RUSC1 RUN and SH3 domain containing 1 1.53 up 0.000079 0.0000014 S100A11 S100 calcium binding protein A11 2.05 up 0.000024 0.0000001 S100A13 S100 calcium binding protein A13 1.56 up 0.000449 0.0000316 S100A16 S100 calcium binding protein A16 1.76 up 0.000047 0.0000005 S100A2 S100 calcium binding protein A2 2.71 up 0.000298 0.0000161 S100A3 S100 calcium binding protein A3 1.95 up 0.000296 0.0000159 S100A6 S100 calcium binding protein A6 1.97 up 0.004309 0.0009295 SAMD4A sterile alpha motif domain containing 4A 1.66 up 0.000493 0.0000376 SAMD5 sterile alpha motif domain containing 5 1.78 up 0.000136 0.0000040 SAP18 Sin3A-associated protein, 18kDa 1.55 up 0.002441 0.0004136 SAR1A secretion associated, Ras related GTPase 1A 1.58 up 0.000030 0.0000002 SAT1 spermidine/spermine N1-acetyltransferase 1 2.49 up 0.000060 0.0000008 SBDS Shwachman-Bodian-Diamond syndrome 1.54 up 0.000878 0.0000932 SBDSP1 Shwachman-Bodian-Diamond syndrome pseudogene 1 1.72 up 0.001029 0.0001193 SBSN suprabasin 2.41 up 0.000398 0.0000258 SCPEP1 serine carboxypeptidase 1 1.73 up 0.000379 0.0000238 SDC1 syndecan 1 1.57 up 0.004621 0.0010248 SDC4 syndecan 4 2.53 up 0.000184 0.0000067 SDE2 SDE2 telomere maintenance homolog (S. pombe) 2.13 up 0.000383 0.0000242 SEC24D SEC24 family member D 1.54 up 0.001067 0.0001258 SEC61A1 Sec61 alpha 1 subunit (S. cerevisiae) 1.66 up 0.001052 0.0001230 SECTM1 secreted and transmembrane 1 1.53 up 0.003922 0.0008082 SELK selenoprotein K 1.58 up 0.000639 0.0000572 SELM selenoprotein M 1.51 up 0.000506 0.0000396 sema domain, immunoglobulin domain (Ig), short basic SEMA3B 2.71 up 0.000097 0.0000020 domain, secreted, (semaphorin) 3B semaphorin 7A, GPI membrane anchor (John Milton Hagen SEMA7A 2.28 up 0.000074 0.0000012 blood group) SEPP1 selenoprotein P, plasma, 1 1.57 up 0.003598 0.0007184 SEPT8 septin 8 1.92 up 0.004290 0.0009234 SERINC1 serine incorporator 1 1.67 up 0.000117 0.0000030 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, SERPINA1 2.06 up 0.003266 0.0006294 antitrypsin), member 1 SERPINB1 serpin peptidase inhibitor, clade B (ovalbumin), member 1 2.03 up 0.000039 0.0000003 SERPINB5 serpin peptidase inhibitor, clade B (ovalbumin), member 5 3.46 up 0.000094 0.0000019 SERPINB8 serpin peptidase inhibitor, clade B (ovalbumin), member 8 3.40 up 0.004304 0.0009278 SERPINC1 serpin peptidase inhibitor, clade C (antithrombin), member 1 2.78 up 0.000104 0.0000024 serpin peptidase inhibitor, clade E (nexin, plasminogen SERPINE1 5.99 up 0.000074 0.0000012 activator inhibitor type 1), member 1 SERPINI1 serpin peptidase inhibitor, clade I (neuroserpin), member 1 2.17 up 0.002965 0.0005449 SERTAD1 SERTA domain containing 1 2.88 up 0.000196 0.0000074 SESN1 sestrin 1 2.64 up 0.000097 0.0000020 SESN2 sestrin 2 1.97 up 0.000565 0.0000474 SFN 4.48 up 0.003156 0.0005973 SGCB sarcoglycan, beta (43kDa -associated glycoprotein) 1.63 up 0.002774 0.0004980 SGK1 serum/glucocorticoid regulated kinase 1 1.84 up 0.000254 0.0000120 SGMS2 sphingomyelin synthase 2 1.86 up 0.000664 0.0000607 SH2B3 SH2B adaptor protein 3 1.94 up 0.003968 0.0008241 SH2D3A SH2 domain containing 3A 1.64 up 0.000129 0.0000036 SH3BGR SH3 domain binding glutamate-rich protein 1.66 up 0.001463 0.0002011 SH3BGRL3 SH3 domain binding glutamate-rich protein like 3 1.51 up 0.000525 0.0000419 SHC (Src homology 2 domain containing) transforming protein SHC1 1.74 up 0.000006 0.0000000 1 SHD Src homology 2 domain containing transforming protein D 1.65 up 0.000067 0.0000010 SHROOM3 shroom family member 3 1.55 up 0.000536 0.0000434 SIRT2 2 1.82 up 0.000500 0.0000386 SIRT4 sirtuin 4 1.86 up 0.001402 0.0001899 SLAMF7 SLAM family member 7 3.34 up 0.000205 0.0000081 SLC10A3 solute carrier family 10, member 3 1.52 up 0.001600 0.0002293 solute carrier family 12 (potassium/chloride transporter), SLC12A4 2.69 up 0.000538 0.0000438 member 4 SLC25A42 solute carrier family 25, member 42 1.69 up 0.000489 0.0000371 SLC27A2 solute carrier family 27 (fatty acid transporter), member 2 1.57 up 0.001733 0.0002576 solute carrier family 29 (equilibrative nucleoside transporter), SLC29A3 1.54 up 0.001218 0.0001529 member 3 SLC30A1 solute carrier family 30 (zinc transporter), member 1 1.60 up 0.000171 0.0000059 SLC30A4 solute carrier family 30 (zinc transporter), member 4 1.83 up 0.000528 0.0000425 SLC31A2 solute carrier family 31 (copper transporter), member 2 1.72 up 0.000626 0.0000553 SLC44A3 solute carrier family 44, member 3 1.60 up 0.004672 0.0010432 SLC48A1 solute carrier family 48 (heme transporter), member 1 1.99 up 0.000088 0.0000016 SLC52A3 solute carrier family 52 (riboflavin transporter), member 3 1.87 up 0.000878 0.0000932 SLC6A6 solute carrier family 6 (neurotransmitter transporter), member 6 1.78 up 0.001432 0.0001955 SMIM14 small integral membrane protein 14 1.76 up 0.000069 0.0000011 SMIM22 small integral membrane protein 22 1.74 up 0.003676 0.0007386 SMIM5 small integral membrane protein 5 3.72 up 0.001520 0.0002136 SMPD1 sphingomyelin phosphodiesterase 1, acid lysosomal 4.18 up 0.000698 0.0000652 SMPDL3A sphingomyelin phosphodiesterase, acid-like 3A 1.59 up 0.003192 0.0006074 SMPDL3B sphingomyelin phosphodiesterase, acid-like 3B 2.02 up 0.001747 0.0002608 SNX2 sorting nexin 2 1.55 up 0.002525 0.0004351 SNX7 sorting nexin 7 1.68 up 0.000120 0.0000031 SOCS4 suppressor of cytokine signaling 4 1.61 up 0.000694 0.0000646 SOD2 superoxide dismutase 2, mitochondrial 1.56 up 0.000307 0.0000169 SORCS2 sortilin-related VPS10 domain containing receptor 2 4.71 up 0.000254 0.0000120 SPAG1 sperm associated antigen 1 2.85 up 0.001362 0.0001807 SPCS3 signal peptidase complex subunit 3 homolog (S. cerevisiae) 1.58 up 0.000051 0.0000006 SPINT1 serine peptidase inhibitor, Kunitz type 1 1.53 up 0.001238 0.0001567 SPNS2 spinster homolog 2 (Drosophila) 3.21 up 0.000120 0.0000032 SPNS3 spinster homolog 3 (Drosophila) 2.37 up 0.001113 0.0001339 SPOCD1 SPOC domain containing 1 2.39 up 0.000864 0.0000908 SPP1 secreted phosphoprotein 1 3.00 up 0.000057 0.0000007 SPTSSA serine palmitoyltransferase, small subunit A 1.55 up 0.002331 0.0003870 SQRDL sulfide quinone reductase-like (yeast) 1.54 up 0.000185 0.0000068 SRP19 signal recognition particle 19kDa 1.97 up 0.001086 0.0001292 SSH2 slingshot protein phosphatase 2 2.51 up 0.000415 0.0000275 SSR1 signal sequence receptor, alpha 1.66 up 0.001924 0.0003001 ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N- ST6GALNAC2 1.80 up 0.000727 0.0000694 acetylgalactosaminide alpha-2,6-sialyltransferase 2 STARD10 StAR-related lipid transfer (START) domain containing 10 1.67 up 0.001661 0.0002422 signal transducer and activator of transcription 3 (acute-phase STAT3 1.57 up 0.000480 0.0000357 response factor) STAT4 signal transducer and activator of transcription 4 2.79 up 0.000294 0.0000158 STMN1 1 4.04 up 0.003044 0.0005664 STOM stomatin 2.08 up 0.000955 0.0001065 STPG1 sperm-tail PG-rich repeat containing 1 1.92 up 0.003962 0.0008227 STX11 syntaxin 11 2.20 up 0.001753 0.0002621 STYK1 serine/threonine/tyrosine kinase 1 2.27 up 0.000261 0.0000127 SULF2 2 3.35 up 0.000107 0.0000025 SULT2B1 sulfotransferase family, cytosolic, 2B, member 1 1.79 up 0.000228 0.0000099 SUN3 Sad1 and UNC84 domain containing 3 1.69 up 0.001199 0.0001491 SUPT7L suppressor of Ty 7 (S. cerevisiae)-like 2.50 up 0.002014 0.0003185 SYK spleen tyrosine kinase 1.66 up 0.000204 0.0000080 SYNE1 spectrin repeat containing, nuclear envelope 1 2.37 up 0.001269 0.0001630 SYNJ1 synaptojanin 1 1.99 up 0.000951 0.0001058 SYT17 synaptotagmin XVII 1.54 up 0.003056 0.0005698 SYTL3 synaptotagmin-like 3 1.52 up 0.002779 0.0004993 TAC3 tachykinin 3 5.10 up 0.000181 0.0000065 TACSTD2 tumor-associated calcium signal transducer 2 3.23 up 0.000277 0.0000140 TAP1 transporter 1, ATP-binding cassette, sub-family B (MDR/TAP) 2.31 up 0.001140 0.0001389 TAPT1 transmembrane anterior posterior transformation 1 1.57 up 0.004519 0.0009929 TBC1D1 TBC1 (tre-2/USP6, BUB2, cdc16) domain family, member 1 1.89 up 0.000288 0.0000150 TBC1D10A TBC1 domain family, member 10A 1.67 up 0.000642 0.0000577 TBC1D2 TBC1 domain family, member 2 2.00 up 0.000063 0.0000009 TBXA2R thromboxane A2 receptor 1.84 up 0.000135 0.0000039 TCF19 transcription factor 19 3.68 up 0.000116 0.0000029 T-cell, immune regulator 1, ATPase, H+ transporting, TCIRG1 1.70 up 0.003526 0.0006977 lysosomal V0 subunit A3 TEP1 -associated protein 1 1.95 up 0.000116 0.0000029 TERF2IP telomeric repeat binding factor 2, interacting protein 2.23 up 0.000219 0.0000091 transcription factor AP-2 gamma (activating enhancer binding TFAP2C 2.12 up 0.000244 0.0000110 protein 2 gamma) TFEB transcription factor EB 1.66 up 0.000294 0.0000157 tissue factor pathway inhibitor (lipoprotein-associated TFPI 1.66 up 0.001684 0.0002470 coagulation inhibitor) TGFA transforming growth factor, alpha 2.84 up 0.000202 0.0000078 TGFB1 transforming growth factor, beta 1 1.63 up 0.000180 0.0000064 TGM1 transglutaminase 1 1.94 up 0.003380 0.0006594 TGM2 transglutaminase 2 2.83 up 0.000237 0.0000105 TGOLN2 trans-golgi network protein 2 1.64 up 0.000102 0.0000022 THAP10 THAP domain containing 10 1.94 up 0.000047 0.0000005 THBD thrombomodulin 2.14 up 0.000247 0.0000113 TICAM1 toll-like receptor adaptor molecule 1 1.52 up 0.000398 0.0000258 TIMP1 TIMP metallopeptidase inhibitor 1 1.62 up 0.000280 0.0000143 TLDC1 TBC/LysM-associated domain containing 1 2.19 up 0.000359 0.0000218 TLR1 toll-like receptor 1 2.37 up 0.000389 0.0000250 TLR3 toll-like receptor 3 4.42 up 0.000042 0.0000004 TM9SF2 transmembrane 9 superfamily member 2 1.60 up 0.000086 0.0000016 TMC8 transmembrane channel-like 8 2.27 up 0.000418 0.0000279 TMCC2 transmembrane and coiled-coil domain family 2 3.04 up 0.000087 0.0000016 TMCC3 transmembrane and coiled-coil domain family 3 1.79 up 0.000047 0.0000005 TMEM106C transmembrane protein 106C 1.54 up 0.000929 0.0001019 TMEM121 transmembrane protein 121 1.72 up 0.002638 0.0004635 TMEM125 transmembrane protein 125 1.84 up 0.000253 0.0000118 TMEM139 transmembrane protein 139 1.98 up 0.000483 0.0000362 TMEM158 transmembrane protein 158 (gene/pseudogene) 1.65 up 0.004428 0.0009656 TMEM159 transmembrane protein 159 1.53 up 0.001380 0.0001847 TMEM173 transmembrane protein 173 1.95 up 0.000059 0.0000008 TMEM185B transmembrane protein 185B 1.84 up 0.002239 0.0003669 TMEM191A transmembrane protein 191A (pseudogene) 1.70 up 0.000432 0.0000295 TMEM191B transmembrane protein 191B 1.71 up 0.000309 0.0000171 TMEM194A transmembrane protein 194A 1.76 up 0.003327 0.0006466 TMEM234 transmembrane protein 234 1.74 up 0.003145 0.0005942 TMEM255B transmembrane protein 255B 1.63 up 0.001052 0.0001230 TMEM38B transmembrane protein 38B 1.70 up 0.001594 0.0002280 TMEM40 transmembrane protein 40 4.37 up 0.000080 0.0000014 TMEM59 transmembrane protein 59 1.99 up 0.000053 0.0000006 TMEM59L transmembrane protein 59-like 1.64 up 0.000103 0.0000023 TMEM61 transmembrane protein 61 2.17 up 0.000041 0.0000003 TMEM79 transmembrane protein 79 2.35 up 0.001892 0.0002932 TMEM92 transmembrane protein 92 1.81 up 0.000715 0.0000675 TMOD1 1.96 up 0.001400 0.0001891 TMOD3 (ubiquitous) 1.62 up 0.000683 0.0000632 TMPRSS4 transmembrane protease, serine 4 3.71 up 0.004608 0.0010200 TMPRSS7 transmembrane protease, serine 7 5.34 up 0.001061 0.0001249 TNFAIP1 tumor necrosis factor, alpha-induced protein 1 (endothelial) 1.84 up 0.000601 0.0000519 TNFAIP2 tumor necrosis factor, alpha-induced protein 2 2.00 up 0.000170 0.0000058 TNFAIP8 tumor necrosis factor, alpha-induced protein 8 1.50 up 0.004547 0.0010017 TNFRSF10A tumor necrosis factor receptor superfamily, member 10a 1.77 up 0.001156 0.0001417 TNFRSF10B tumor necrosis factor receptor superfamily, member 10b 1.89 up 0.000384 0.0000244 tumor necrosis factor receptor superfamily, member 10c, decoy TNFRSF10C 2.62 up 0.000865 0.0000910 without an intracellular domain tumor necrosis factor receptor superfamily, member 10d, decoy TNFRSF10D 1.83 up 0.000216 0.0000089 with truncated death domain TNFRSF25 tumor necrosis factor receptor superfamily, member 25 1.61 up 0.004670 0.0010418 TNFRSF6B tumor necrosis factor receptor superfamily, member 6b, decoy 1.80 up 0.000427 0.0000288 TNK2 tyrosine kinase, non-receptor, 2 1.54 up 0.000205 0.0000081 TNNC1 type 1 (slow) 1.78 up 0.001404 0.0001902 TNNI2 troponin I type 2 (skeletal, fast) 6.95 up 0.000456 0.0000326 TNXB tenascin XB 1.80 up 0.001240 0.0001572 TOB1 transducer of ERBB2, 1 1.66 up 0.000268 0.0000132 TOR1B torsin family 1, member B (torsin B) 1.68 up 0.000201 0.0000077 TP53I11 tumor protein p53 inducible protein 11 1.59 up 0.000448 0.0000315 TP53I3 tumor protein p53 inducible protein 3 5.24 up 0.000027 0.0000001 TP53INP1 tumor protein p53 inducible nuclear protein 1 3.71 up 0.000051 0.0000006 TPM1 tropomyosin 1 (alpha) 1.67 up 0.004689 0.0010475 TPST1 tyrosylprotein sulfotransferase 1 1.55 up 0.000505 0.0000394 TRAF4 TNF receptor-associated factor 4 1.75 up 0.000205 0.0000082 TRAPPC2P1 trafficking protein particle complex 2 pseudogene 1 1.61 up 0.000482 0.0000361 TRIAP1 TP53 regulated inhibitor of apoptosis 1 2.10 up 0.000136 0.0000040 TRIM15 tripartite motif containing 15 2.05 up 0.003232 0.0006176 TRIM29 tripartite motif containing 29 3.36 up 0.000630 0.0000558 TRIM68 tripartite motif containing 68 1.65 up 0.000710 0.0000666 TRIM8 tripartite motif containing 8 2.05 up 0.000046 0.0000005 TRIML2 tripartite motif family-like 2 2.33 up 0.000149 0.0000046 TRIP6 thyroid hormone receptor interactor 6 1.72 up 0.000743 0.0000722 TSC22D3 TSC22 domain family, member 3 2.14 up 0.000858 0.0000897 TSPAN1 tetraspanin 1 2.24 up 0.000026 0.0000001 TSPAN14 tetraspanin 14 1.65 up 0.000406 0.0000266 TSPAN7 tetraspanin 7 1.66 up 0.000723 0.0000688 TSPYL4 TSPY-like 4 1.56 up 0.000528 0.0000423 TTC28-AS1 TTC28 antisense RNA 1 4.99 up 0.000396 0.0000255 TTC39A tetratricopeptide repeat domain 39A 1.63 up 0.000336 0.0000197 TUFT1 tuftelin 1 2.29 up 0.000136 0.0000040 TXNDC17 thioredoxin domain containing 17 1.61 up 0.000740 0.0000711 UBC ubiquitin C 1.60 up 0.001959 0.0003075 UBFD1 ubiquitin family domain containing 1 2.28 up 0.000045 0.0000005 UBL3 ubiquitin-like 3 1.66 up 0.000554 0.0000460 UCK1 uridine-cytidine kinase 1 1.55 up 0.003060 0.0005715 UCN2 urocortin 2 2.02 up 0.001219 0.0001531 UFD1L ubiquitin fusion degradation 1 like (yeast) 1.63 up 0.000298 0.0000162 ubiquitin-like with PHD and ring finger domains 2, E3 UHRF2 1.61 up 0.000089 0.0000017 ubiquitin protein ligase ULBP2 UL16 binding protein 2 4.29 up 0.000027 0.0000001 ULK1 unc-51 like autophagy activating kinase 1 1.69 up 0.000026 0.0000001 ULK4P1 ULK4 pseudogene 1 1.64 up 0.001592 0.0002270 UNC13D unc-13 homolog D (C. elegans) 2.08 up 0.002277 0.0003744 UNC5B-AS1 UNC5B antisense RNA 1 5.23 up 0.000041 0.0000003 UPP1 uridine phosphorylase 1 2.09 up 0.000117 0.0000030 USP11 ubiquitin specific peptidase 11 1.58 up 0.003486 0.0006860 USP18 ubiquitin specific peptidase 18 1.84 up 0.000782 0.0000780 USP35 ubiquitin specific peptidase 35 1.86 up 0.000582 0.0000495 USP53 ubiquitin specific peptidase 53 1.65 up 0.000742 0.0000717 VAMP8 vesicle-associated membrane protein 8 1.80 up 0.000228 0.0000099 VASN vasorin 1.91 up 0.000977 0.0001105 VCAN versican 1.70 up 0.000317 0.0000178 VDR vitamin D (1,25- dihydroxyvitamin D3) receptor 1.57 up 0.000548 0.0000450 VEPH1 ventricular zone expressed PH domain-containing 1 1.79 up 0.004307 0.0009287 VPS37D vacuolar protein sorting 37 homolog D (S. cerevisiae) 1.55 up 0.000309 0.0000171 WBSCR28 Williams-Beuren syndrome chromosome region 28 2.90 up 0.001121 0.0001353 WFDC1 WAP four-disulfide core domain 1 3.36 up 0.000041 0.0000003 WAS protein homolog associated with actin, golgi membranes WHAMM 1.75 up 0.000047 0.0000005 and microtubules WIPI1 WD repeat domain, phosphoinositide interacting 1 1.50 up 0.001026 0.0001188 WLS wntless Wnt ligand secretion mediator 1.76 up 0.001658 0.0002410 WNT7A wingless-type MMTV integration site family, member 7A 7.33 up 0.000380 0.0000240 WNT7B wingless-type MMTV integration site family, member 7B 2.67 up 0.000613 0.0000534 WRAP73 WD repeat containing, antisense to TP73 1.54 up 0.000750 0.0000730 WWTR1 WW domain containing transcription regulator 1 2.46 up 0.000029 0.0000002 X-ray repair complementing defective repair in Chinese XRCC3 1.55 up 0.001238 0.0001568 hamster cells 3 YBX3 Y box binding protein 3 1.53 up 0.000505 0.0000395 YPEL3 yippee-like 3 (Drosophila) 4.72 up 0.000195 0.0000074 YPEL5 yippee-like 5 (Drosophila) 2.63 up 0.000020 0.0000000 ZCCHC12 zinc finger, CCHC domain containing 12 2.80 up 0.000915 0.0000992 ZFP36L2 ZFP36 ring finger protein-like 2 1.51 up 0.000162 0.0000052 ZFYVE1 zinc finger, FYVE domain containing 1 2.17 up 0.000092 0.0000018 ZNF177 zinc finger protein 177 1.50 up 0.002753 0.0004917 ZNF219 zinc finger protein 219 2.18 up 0.000060 0.0000008 ZNF226 zinc finger protein 226 1.65 up 0.001237 0.0001564 ZNF250 zinc finger protein 250 1.62 up 0.000670 0.0000614 ZNF34 zinc finger protein 34 1.85 up 0.001520 0.0002132 ZNF341 zinc finger protein 341 1.51 up 0.000301 0.0000165 ZNF354B zinc finger protein 354B 1.85 up 0.003912 0.0008056 ZNF416 zinc finger protein 416 1.52 up 0.003985 0.0008294 ZNF430 zinc finger protein 430 1.62 up 0.003974 0.0008264 ZNF442 zinc finger protein 442 1.63 up 0.001925 0.0003003 ZNF488 zinc finger protein 488 1.74 up 0.003256 0.0006264 ZNF555 zinc finger protein 555 1.59 up 0.000347 0.0000210 ZNF564 zinc finger protein 564 1.70 up 0.002145 0.0003464 ZNF600 zinc finger protein 600 2.15 up 0.000231 0.0000101 ZNF641 zinc finger protein 641 1.55 up 0.000864 0.0000908 ZNF654 zinc finger protein 654 2.08 up 0.000217 0.0000089 ZNF672 zinc finger protein 672 1.55 up 0.001119 0.0001349 ZNF684 zinc finger protein 684 1.89 up 0.004137 0.0008731 ZNF703 zinc finger protein 703 2.57 up 0.001220 0.0001533 ZNF79 zinc finger protein 79 2.75 up 0.000014 0.0000000 zinc finger (CCCH type), RNA-binding motif and ZRSR2 1.61 up 0.000261 0.0000127 serine/arginine rich 2 ZSCAN20 zinc finger and SCAN domain containing 20 1.61 up 0.000802 0.0000808 ZSWIM3 zinc finger, SWIM-type containing 3 2.44 up 0.000515 0.0000409

A2M-AS1 A2M antisense RNA 1 1.61 down 0.003309 0.0006414 AAAS achalasia, adrenocortical insufficiency, alacrimia 1.60 down 0.003817 0.0007749 AATK apoptosis-associated tyrosine kinase 5.66 down 0.000014 0.0000000 ABHD11 abhydrolase domain containing 11 1.58 down 0.000803 0.0000809 ABHD14B abhydrolase domain containing 14B 1.68 down 0.000916 0.0000994 ABLIM2 actin binding LIM , member 2 7.05 down 0.000532 0.0000429 ACACA acetyl-CoA carboxylase alpha 1.52 down 0.000366 0.0000227 ACAD9 acyl-CoA dehydrogenase family, member 9 1.62 down 0.000103 0.0000023 ACADS acyl-CoA dehydrogenase, C-2 to C-3 short chain 1.64 down 0.004722 0.0010563 ACADSB acyl-CoA dehydrogenase, short/branched chain 2.01 down 0.000376 0.0000235 1-aminocyclopropane-1-carboxylate synthase homolog ACCS 2.09 down 0.000442 0.0000307 (Arabidopsis)(non-functional) ACSL3 acyl-CoA synthetase long-chain family member 3 2.58 down 0.000565 0.0000474 ACSL5 acyl-CoA synthetase long-chain family member 5 1.89 down 0.000066 0.0000010 ACSM3 acyl-CoA synthetase medium-chain family member 3 1.80 down 0.000548 0.0000451 ACTR1B ARP1 actin-related protein 1 homolog B, centractin beta (yeast) 1.59 down 0.001006 0.0001155 ACTR3B ARP3 actin-related protein 3 homolog B (yeast) 1.79 down 0.000459 0.0000330 ADCK1 aarF domain containing kinase 1 3.18 down 0.002012 0.0003180 ADCY3 adenylate cyclase 3 1.59 down 0.000656 0.0000594 AEBP2 AE binding protein 2 1.51 down 0.000074 0.0000012 AFAP1 actin filament associated protein 1 1.64 down 0.001911 0.0002971 AGFG1 ArfGAP with FG repeats 1 2.30 down 0.004440 0.0009698 AGGF1 angiogenic factor with G patch and FHA domains 1 1.79 down 0.000114 0.0000028 AGPAT5 1-acylglycerol-3-phosphate O-acyltransferase 5 2.07 down 0.000028 0.0000002 AGPS alkylglycerone phosphate synthase 2.64 down 0.000102 0.0000022 aminoacyl tRNA synthetase complex-interacting AIMP2 1.63 down 0.001371 0.0001826 multifunctional protein 2 AK2 2 1.99 down 0.000259 0.0000125 AK8 adenylate kinase 8 1.63 down 0.001070 0.0001266 AKT2 v-akt murine thymoma viral oncogene homolog 2 1.71 down 0.001974 0.0003102 ALKBH3 alkB, alkylation repair homolog 3 (E. coli) 1.55 down 0.001059 0.0001245 AMD1 adenosylmethionine decarboxylase 1 1.78 down 0.000459 0.0000331 ANAPC1 anaphase promoting complex subunit 1 1.65 down 0.002028 0.0003213 ANKRD11 ankyrin repeat domain 11 1.55 down 0.003098 0.0005826 ANKRD18DP ankyrin repeat domain 18D, pseudogene 2.49 down 0.004325 0.0009343 ANKRD28 ankyrin repeat domain 28 1.53 down 0.004395 0.0009538 acidic (leucine-rich) nuclear phosphoprotein 32 family, member ANP32B 1.69 down 0.000206 0.0000082 B acidic (leucine-rich) nuclear phosphoprotein 32 family, member ANP32E 1.56 down 0.001170 0.0001442 E AOC3 amine oxidase, copper containing 3 1.64 down 0.001775 0.0002669 AP1S3 adaptor-related protein complex 1, sigma 3 subunit 1.52 down 0.004866 0.0010984 APEH acylaminoacyl-peptide hydrolase 1.57 down 0.000692 0.0000643 APOM apolipoprotein M 2.87 down 0.001335 0.0001753 ARFRP1 ADP-ribosylation factor related protein 1 2.53 down 0.000664 0.0000606 ARHGAP11A Rho GTPase activating protein 11A 2.25 down 0.000250 0.0000116 ARHGAP11B Rho GTPase activating protein 11B 1.79 down 0.000364 0.0000225 ARHGAP19 Rho GTPase activating protein 19 2.57 down 0.000505 0.0000394 ARHGAP26 Rho GTPase activating protein 26 1.93 down 0.001230 0.0001552 ARHGAP35 Rho GTPase activating protein 35 1.50 down 0.000219 0.0000091 ARHGAP5 Rho GTPase activating protein 5 2.32 down 0.001775 0.0002673 ARHGEF39 Rho guanine nucleotide exchange factor (GEF) 39 2.52 down 0.000872 0.0000921 ARID2 AT rich interactive domain 2 (ARID, RFX-like) 1.78 down 0.000938 0.0001036 ARIH2 ariadne RBR E3 ubiquitin protein ligase 2 1.78 down 0.000022 0.0000001 ARL4A ADP-ribosylation factor-like 4A 1.65 down 0.000049 0.0000005 ARL6IP1 ADP-ribosylation factor-like 6 interacting protein 1 1.53 down 0.000057 0.0000007 ARMC3 armadillo repeat containing 3 2.70 down 0.003706 0.0007469 ARMC4 armadillo repeat containing 4 1.70 down 0.000774 0.0000768 ARMC8 armadillo repeat containing 8 1.87 down 0.003021 0.0005610 ASB13 ankyrin repeat and SOCS box containing 13 1.54 down 0.002761 0.0004937 ASIC1 acid-sensing (proton-gated) ion channel 1 1.61 down 0.001175 0.0001452 asp (abnormal spindle) homolog, microcephaly associated ASPM 2.27 down 0.000569 0.0000479 (Drosophila) ASPRV1 aspartic peptidase, retroviral-like 1 2.08 down 0.002318 0.0003843 ATAD2B ATPase family, AAA domain containing 2B 2.04 down 0.000698 0.0000651 ATF4 activating transcription factor 4 1.59 down 0.004046 0.0008473 ATF7IP activating transcription factor 7 interacting protein 1.62 down 0.000006 0.0000000 ATP11C ATPase, class VI, type 11C 1.62 down 0.000253 0.0000118 ATP6V1E2 ATPase, H+ transporting, lysosomal 31kDa, V1 subunit E2 2.09 down 0.000297 0.0000161 ATR ataxia telangiectasia and Rad3 related 1.51 down 0.000794 0.0000799 ATXN10 ataxin 10 1.62 down 0.000644 0.0000579 ATXN1L ataxin 1-like 1.50 down 0.004158 0.0008814 AURKA A 2.15 down 0.000280 0.0000143 AURKAPS1 aurora kinase A pseudogene 1 1.96 down 0.000121 0.0000032 AXIN2 axin 2 2.30 down 0.002618 0.0004582 AZI2 5-azacytidine induced 2 1.55 down 0.001676 0.0002455 AZIN1 antizyme inhibitor 1 1.61 down 0.000601 0.0000520 B3GALNT2 beta-1,3-N-acetylgalactosaminyltransferase 2 1.55 down 0.001084 0.0001289 B9D1 B9 protein domain 1 1.63 down 0.000477 0.0000351 BAHCC1 BAH domain and coiled-coil containing 1 1.54 down 0.003685 0.0007410 BAIAP2 BAI1-associated protein 2 2.09 down 0.000713 0.0000671 BANK1 B-cell with ankyrin repeats 1 2.53 down 0.000047 0.0000005 BCKDHB branched chain keto acid dehydrogenase E1, beta polypeptide 1.54 down 0.003890 0.0007980 BCL2L12 BCL2-like 12 (proline rich) 1.50 down 0.000798 0.0000803 BCOR BCL6 corepressor 2.86 down 0.000480 0.0000356 BCR breakpoint cluster region 1.78 down 0.000271 0.0000135 BDNF brain-derived neurotrophic factor 2.28 down 0.000791 0.0000793 BEND3 BEN domain containing 3 2.39 down 0.000102 0.0000022 BET1 Bet1 golgi vesicular membrane trafficking protein 1.90 down 0.001369 0.0001822 BIRC5 baculoviral IAP repeat containing 5 1.50 down 0.000362 0.0000221 BMP4 bone morphogenetic protein 4 1.67 down 0.000120 0.0000031 BORA bora, aurora kinase A activator 1.69 down 0.000477 0.0000351 BPHL biphenyl hydrolase-like (serine hydrolase) 1.82 down 0.000624 0.0000549 BRWD1 bromodomain and WD repeat domain containing 1 2.38 down 0.000159 0.0000051 BUB1 BUB1 mitotic checkpoint serine/threonine kinase 2.07 down 0.000103 0.0000023 BUB1B BUB1 mitotic checkpoint serine/threonine kinase B 2.26 down 0.000117 0.0000030 C17orf82 chromosome 17 open reading frame 82 1.82 down 0.001600 0.0002292 C1orf213 chromosome 1 open reading frame 213 1.56 down 0.003880 0.0007927 C1orf233 chromosome 1 open reading frame 233 1.51 down 0.003820 0.0007758 C1RL complement component 1, r subcomponent-like 2.21 down 0.000844 0.0000867 C2orf68 chromosome 2 open reading frame 68 1.66 down 0.003029 0.0005632 C2orf69 chromosome 2 open reading frame 69 1.54 down 0.001543 0.0002180 C3AR1 complement component 3a receptor 1 1.68 down 0.001317 0.0001723 C6orf62 chromosome 6 open reading frame 62 1.55 down 0.001342 0.0001769 C7orf50 open reading frame 50 1.95 down 0.002620 0.0004590 C8orf37 chromosome 8 open reading frame 37 1.73 down 0.002421 0.0004081 C9orf171 chromosome 9 open reading frame 171 2.11 down 0.000377 0.0000236 CACNA1B calcium channel, voltage-dependent, N type, alpha 1B subunit 2.25 down 0.001590 0.0002264 CACNA2D2 calcium channel, voltage-dependent, alpha 2/delta subunit 2 1.99 down 0.000253 0.0000118 CACYBP calcyclin binding protein 1.72 down 0.000662 0.0000602 CALML4 calmodulin-like 4 2.20 down 0.000022 0.0000001 CAMKK1 calcium/calmodulin-dependent protein kinase kinase 1, alpha 1.86 down 0.004053 0.0008497 CAMKK2 calcium/calmodulin-dependent protein kinase kinase 2, beta 1.81 down 0.004461 0.0009764 CASC5 cancer susceptibility candidate 5 1.77 down 0.000194 0.0000073 core-binding factor, runt domain, alpha subunit 2; translocated CBFA2T3 1.71 down 0.000332 0.0000194 to, 3 CBX6 chromobox homolog 6 1.71 down 0.000941 0.0001043 CC2D2A coiled-coil and C2 domain containing 2A 2.25 down 0.000786 0.0000786 CCDC106 coiled-coil domain containing 106 1.64 down 0.000548 0.0000451 CCDC121 coiled-coil domain containing 121 2.02 down 0.000335 0.0000197 CCDC146 coiled-coil domain containing 146 1.55 down 0.003652 0.0007318 CCDC167 coiled-coil domain containing 167 1.59 down 0.000345 0.0000207 CCDC18 coiled-coil domain containing 18 2.52 down 0.001020 0.0001174 CCDC88C coiled-coil domain containing 88C 1.55 down 0.002499 0.0004279 CCNB1 cyclin B1 2.21 down 0.000022 0.0000001 CCNB2 cyclin B2 1.72 down 0.001801 0.0002723 CCNL2 cyclin L2 2.29 down 0.000141 0.0000042 CD3EAP CD3e molecule, epsilon associated protein 1.53 down 0.000057 0.0000007 CDC20 cell division cycle 20 2.46 down 0.000197 0.0000075 CDCA7 cell division cycle associated 7 1.90 down 0.000227 0.0000098 CDCA8 cell division cycle associated 8 1.52 down 0.002155 0.0003487 CDKN3 cyclin-dependent kinase inhibitor 3 2.25 down 0.000006 0.0000000 CDPF1 cysteine-rich, DPF motif domain containing 1 1.90 down 0.000045 0.0000004 CDV3 CDV3 homolog (mouse) 1.51 down 0.002355 0.0003933 CENPA centromere protein A 1.66 down 0.000032 0.0000002 CENPE centromere protein E, 312kDa 1.88 down 0.000022 0.0000001 CENPF centromere protein F, 350/400kDa 1.98 down 0.002923 0.0005337 CEP70 centrosomal protein 70kDa 1.65 down 0.000352 0.0000213 CEP83 centrosomal protein 83kDa 1.60 down 0.002516 0.0004317 CHDH choline dehydrogenase 1.95 down 0.000515 0.0000410 CHRNA5 cholinergic receptor, nicotinic, alpha 5 (neuronal) 1.51 down 0.001696 0.0002492 CIRBP cold inducible RNA binding protein 1.56 down 0.000091 0.0000018 CKAP5 cytoskeleton associated protein 5 1.51 down 0.000639 0.0000572 CLASP2 cytoplasmic linker associated protein 2 1.56 down 0.001267 0.0001626 CLCN2 chloride channel, voltage-sensitive 2 1.54 down 0.000958 0.0001073 CLUAP1 clusterin associated protein 1 1.75 down 0.000306 0.0000168 CLYBL citrate beta like 1.99 down 0.000372 0.0000233 CNTRL centriolin 2.49 down 0.000152 0.0000048 COA5 cytochrome c oxidase assembly factor 5 1.88 down 0.000732 0.0000699 COQ2 coenzyme Q2 4-hydroxybenzoate polyprenyltransferase 1.66 down 0.001805 0.0002736 COQ3 coenzyme Q3 1.96 down 0.001478 0.0002041 CPOX coproporphyrinogen oxidase 1.64 down 0.001790 0.0002704 CREB3L4 cAMP responsive element binding protein 3-like 4 1.84 down 0.000938 0.0001036 CRTC1 CREB regulated transcription coactivator 1 2.36 down 0.000305 0.0000168 CRYL1 crystallin, lambda 1 1.96 down 0.000274 0.0000137 CRYZ crystallin, zeta (quinone reductase) 1.68 down 0.000543 0.0000444 CSE1L CSE1 chromosome segregation 1-like (yeast) 1.54 down 0.000573 0.0000484 CSNK2A2 , alpha prime polypeptide 1.60 down 0.000210 0.0000085 CTAGE5 CTAGE family, member 5 1.54 down 0.002532 0.0004366 CTPS2 CTP synthase 2 1.59 down 0.000481 0.0000359 CUTC cutC copper transporter 2.05 down 0.000275 0.0000138 CYB5B cytochrome b5 type B (outer mitochondrial membrane) 2.09 down 0.000350 0.0000211 CYB5RL cytochrome b5 reductase-like 2.30 down 0.000351 0.0000212 DAK dihydroxyacetone kinase 2 homolog (S. cerevisiae) 1.83 down 0.000174 0.0000061 DCBLD2 discoidin, CUB and LCCL domain containing 2 1.57 down 0.001195 0.0001482 DCUN1D4 DCN1, defective in cullin neddylation 1, domain containing 4 1.93 down 0.000502 0.0000389 DDN dendrin 1.86 down 0.000833 0.0000849 DDX46 DEAD (Asp-Glu-Ala-Asp) box polypeptide 46 1.57 down 0.001235 0.0001561 DENND4C DENN/MADD domain containing 4C 1.69 down 0.001242 0.0001577 DENND5B DENN/MADD domain containing 5B 2.22 down 0.002279 0.0003752 DEPDC1 DEP domain containing 1 2.54 down 0.000054 0.0000006 DEPDC1B DEP domain containing 1B 1.87 down 0.000336 0.0000198 DET1 de-etiolated homolog 1 (Arabidopsis) 1.53 down 0.001396 0.0001878 DHRS2 dehydrogenase/reductase (SDR family) member 2 2.94 down 0.000022 0.0000001 DHRS3 dehydrogenase/reductase (SDR family) member 3 1.61 down 0.000253 0.0000119 DHRS4-AS1 DHRS4 antisense RNA 1 1.74 down 0.003533 0.0007007 DHX32 DEAH (Asp-Glu-Ala-His) box polypeptide 32 1.63 down 0.000222 0.0000094 DIDO1 death inducer-obliterator 1 1.55 down 0.001501 0.0002093 DIEXF digestive organ expansion factor homolog (zebrafish) 1.57 down 0.001026 0.0001189 DIMT1 DIM1 dimethyladenosine transferase 1 homolog (S. cerevisiae) 2.59 down 0.000305 0.0000168 DIS3L DIS3 like exosome 3'-5' 1.76 down 0.000353 0.0000214 DLEU2L deleted in lymphocytic leukemia 2-like 1.98 down 0.000933 0.0001026 DLG1 discs, large homolog 1 (Drosophila) 1.63 down 0.002278 0.0003749 DLG5-AS1 DLG5 antisense RNA 1 1.81 down 0.002707 0.0004805 DLGAP5 discs, large (Drosophila) homolog-associated protein 5 1.95 down 0.000589 0.0000504 DNM1L dynamin 1-like 1.51 down 0.002788 0.0005025 DNMT3B DNA (cytosine-5-)-methyltransferase 3 beta 1.64 down 0.000380 0.0000239 DOCK1 dedicator of cytokinesis 1 1.54 down 0.000062 0.0000009 DOK3 docking protein 3 1.87 down 0.000851 0.0000886 dolichyl-phosphate mannosyltransferase polypeptide 1, DPM1 1.54 down 0.001166 0.0001432 catalytic subunit DPP8 dipeptidyl-peptidase 8 1.60 down 0.000074 0.0000012 DRD4 dopamine receptor D4 5.42 down 0.001704 0.0002513 DTD1 D-tyrosyl-tRNA deacylase 1 1.64 down 0.000495 0.0000380 dual-specificity tyrosine-(Y)-phosphorylation regulated kinase DYRK2 1.85 down 0.000254 0.0000121 2 EBPL emopamil binding protein-like 2.31 down 0.000505 0.0000393 EEF2K eukaryotic elongation factor-2 kinase 2.91 down 0.000037 0.0000002 EFCC1 EF-hand and coiled-coil domain containing 1 1.79 down 0.002990 0.0005528 EHBP1 EH domain binding protein 1 1.62 down 0.001253 0.0001596 EHMT1 euchromatic histone-lysine N-methyltransferase 1 1.86 down 0.003252 0.0006233 eukaryotic translation initiation factor 2B, subunit 5 epsilon, EIF2B5 1.74 down 0.000121 0.0000032 82kDa EIF4B eukaryotic translation initiation factor 4B 1.77 down 0.001330 0.0001745 EIF4E eukaryotic translation initiation factor 4E 1.82 down 0.003446 0.0006755 EIF4E2 eukaryotic translation initiation factor 4E family member 2 1.75 down 0.000458 0.0000330 EIF5 eukaryotic translation initiation factor 5 1.85 down 0.000621 0.0000545 EMC2 ER membrane protein complex subunit 2 1.50 down 0.000400 0.0000261 EML4 echinoderm microtubule associated protein like 4 1.59 down 0.000250 0.0000114 ENDOV V 1.52 down 0.000613 0.0000533 ENKD1 enkurin domain containing 1 2.20 down 0.000103 0.0000023 ENOX2 ecto-NOX disulfide-thiol exchanger 2 1.60 down 0.000501 0.0000389 EP400 E1A binding protein p400 1.77 down 0.003957 0.0008199 EPB41L4A-AS1 EPB41L4A antisense RNA 1 1.96 down 0.000094 0.0000019 EPHX2 epoxide hydrolase 2, cytoplasmic 1.69 down 0.000060 0.0000008 EPS15 epidermal growth factor receptor pathway substrate 15 1.75 down 0.002023 0.0003204 ERMARD ER membrane-associated RNA degradation 1.71 down 0.000383 0.0000243 ETF1 eukaryotic translation termination factor 1 1.61 down 0.000577 0.0000490 EVI5 ecotropic viral integration site 5 1.68 down 0.004535 0.0009982 EWSR1 EWS RNA-binding protein 1 1.86 down 0.001676 0.0002453 EXD3 exonuclease 3'-5' domain containing 3 3.82 down 0.000075 0.0000013 EXOC6 exocyst complex component 6 1.59 down 0.001533 0.0002162 FAM13B family with sequence similarity 13, member B 1.62 down 0.001349 0.0001784 FAM149B1 family with sequence similarity 149, member B1 2.61 down 0.000322 0.0000184 FAM175A family with sequence similarity 175, member A 2.79 down 0.000036 0.0000002 FAM203A family with sequence similarity 203, member A 2.32 down 0.000205 0.0000081 FAM216A family with sequence similarity 216, member A 1.75 down 0.000936 0.0001031 FAM72A family with sequence similarity 72, member A 2.08 down 0.000043 0.0000004 FAM72D family with sequence similarity 72, member D 2.18 down 0.000103 0.0000023 FAM86FP family with sequence similarity 86, member A pseudogene 2.00 down 0.000078 0.0000013 FASTKD2 FAST kinase domains 2 1.77 down 0.002106 0.0003382 FBRSL1 fibrosin-like 1 1.54 down 0.000415 0.0000275 FBXO18 F-box protein, helicase, 18 1.51 down 0.003884 0.0007946 FBXO24 F-box protein 24 1.97 down 0.004725 0.0010580 FBXO4 F-box protein 4 1.80 down 0.004152 0.0008787 FBXO9 F-box protein 9 1.64 down 0.000360 0.0000219 FGF9 fibroblast growth factor 9 4.09 down 0.000456 0.0000327 FGGY FGGY carbohydrate kinase domain containing 1.64 down 0.004071 0.0008545 FHAD1 forkhead-associated (FHA) phosphopeptide binding domain 1 1.93 down 0.002470 0.0004203 FJX1 four jointed box 1 (Drosophila) 1.75 down 0.000864 0.0000906 FKBP5 FK506 binding protein 5 1.63 down 0.004075 0.0008554 FLYWCH1 FLYWCH-type zinc finger 1 1.80 down 0.001059 0.0001246 FNBP4 formin binding protein 4 1.62 down 0.000990 0.0001127 FOXK2 forkhead box K2 1.57 down 0.000329 0.0000190 FRMD5 FERM domain containing 5 1.75 down 0.002895 0.0005277 FUBP3 far upstream element (FUSE) binding protein 3 1.51 down 0.000923 0.0001008 FUOM fucose mutarotase 1.62 down 0.001594 0.0002280 FXR1 fragile X mental retardation, autosomal homolog 1 1.97 down 0.000831 0.0000847 G2E3 G2/M-phase specific E3 ubiquitin protein ligase 1.82 down 0.000390 0.0000251 G3BP1 GTPase activating protein (SH3 domain) binding protein 1 1.62 down 0.000167 0.0000056 GAS2L3 growth arrest-specific 2 like 3 2.00 down 0.000344 0.0000206 GATAD2A GATA zinc finger domain containing 2A 1.58 down 0.000447 0.0000313 GBAS glioblastoma amplified sequence 1.60 down 0.001020 0.0001176 GCLC glutamate-cysteine ligase, catalytic subunit 1.81 down 0.000477 0.0000351 GCOM1 GRINL1A complex locus 1 1.51 down 0.000709 0.0000664 GDI2 GDP dissociation inhibitor 2 1.50 down 0.002521 0.0004339 GEN1 GEN1 Holliday junction 5' flap endonuclease 1.92 down 0.001167 0.0001436 golgi-associated, gamma adaptin ear containing, ARF binding GGA2 1.75 down 0.000159 0.0000051 protein 2 GHRLOS ghrelin opposite strand/antisense RNA 2.78 down 0.000321 0.0000182 GLT8D1 glycosyltransferase 8 domain containing 1 1.56 down 0.002992 0.0005532 GLTSCR2 glioma tumor suppressor candidate region gene 2 1.89 down 0.000409 0.0000269 guanine nucleotide binding protein (G protein), alpha z GNAZ 2.32 down 0.000037 0.0000002 polypeptide guanine nucleotide binding protein (G protein), beta GNB1L 2.05 down 0.000242 0.0000108 polypeptide 1-like GNL3 guanine nucleotide binding protein-like 3 (nucleolar) 1.68 down 0.002959 0.0005434 GNL3L guanine nucleotide binding protein-like 3 (nucleolar)-like 1.55 down 0.000244 0.0000110 GOLGA3 golgin A3 1.51 down 0.001648 0.0002386 GP9 glycoprotein IX (platelet) 1.64 down 0.001904 0.0002955 GPR180 G protein-coupled receptor 180 1.58 down 0.002040 0.0003233 GRID1 glutamate receptor, ionotropic, delta 1 1.87 down 0.000674 0.0000620 GRK6 G protein-coupled receptor kinase 6 1.53 down 0.003665 0.0007356 GSTZ1 glutathione S-transferase zeta 1 1.94 down 0.000528 0.0000423 GYLTL1B glycosyltransferase-like 1B 1.53 down 0.002123 0.0003421 H1FX H1 histone family, member X 1.74 down 0.000733 0.0000701 H2AFX H2A histone family, member X 2.07 down 0.000152 0.0000048 HABP4 hyaluronan binding protein 4 1.74 down 0.000652 0.0000590 HECT domain and ankyrin repeat containing E3 ubiquitin HACE1 1.57 down 0.001823 0.0002785 protein ligase 1 HAUS6 HAUS augmin-like complex, subunit 6 2.76 down 0.002690 0.0004760 HDAC4 histone deacetylase 4 3.64 down 0.000057 0.0000007 HEATR3 HEAT repeat containing 3 1.76 down 0.000532 0.0000429 hexosaminidase (glycosyl hydrolase family 20, catalytic HEXDC 1.52 down 0.002232 0.0003653 domain) containing HIATL1 hippocampus abundant transcript-like 1 1.50 down 0.002894 0.0005275 HIBCH 3-hydroxyisobutyryl-CoA hydrolase 1.58 down 0.004204 0.0008980 HIRA histone cell cycle regulator 1.97 down 0.000015 0.0000000 HIST1H1C histone cluster 1, H1c 2.29 down 0.000177 0.0000062 HIST1H1D histone cluster 1, H1d 3.42 down 0.000091 0.0000018 HIST1H1E histone cluster 1, H1e 3.36 down 0.000010 0.0000000 HIST1H2AB histone cluster 1, H2ab 4.16 down 0.000087 0.0000016 HIST1H2AC histone cluster 1, H2ac 4.16 down 0.000083 0.0000015 HIST1H2AD histone cluster 1, H2ad 2.59 down 0.000014 0.0000000 HIST1H2AE histone cluster 1, H2ae 2.68 down 0.000043 0.0000004 HIST1H2AH histone cluster 1, H2ah 3.47 down 0.000006 0.0000000 HIST1H2AI histone cluster 1, H2ai 3.64 down 0.000044 0.0000004 HIST1H2AJ histone cluster 1, H2aj 3.07 down 0.000014 0.0000000 HIST1H2AK histone cluster 1, H2ak 3.39 down 0.000014 0.0000000 HIST1H2AM histone cluster 1, H2am 4.29 down 0.000033 0.0000002 HIST1H2BB histone cluster 1, H2bb 2.23 down 0.000205 0.0000081 HIST1H2BC histone cluster 1, H2bc 2.46 down 0.000040 0.0000003 HIST1H2BD histone cluster 1, H2bd 1.65 down 0.000591 0.0000507 HIST1H2BF histone cluster 1, H2bf 7.85 down 0.000459 0.0000331 HIST1H2BG histone cluster 1, H2bg 2.45 down 0.000127 0.0000035 HIST1H2BH histone cluster 1, H2bh 1.83 down 0.000158 0.0000050 HIST1H2BI histone cluster 1, H2bi 1.52 down 0.000102 0.0000021 HIST1H2BJ histone cluster 1, H2bj 3.02 down 0.000022 0.0000001 HIST1H2BK histone cluster 1, H2bk 1.89 down 0.000228 0.0000099 HIST1H2BL histone cluster 1, H2bl 1.80 down 0.000967 0.0001089 HIST1H2BO histone cluster 1, H2bo 1.90 down 0.000079 0.0000014 HIST1H3B histone cluster 1, H3b 2.77 down 0.000017 0.0000000 HIST1H3D histone cluster 1, H3d 3.48 down 0.000015 0.0000000 HIST1H3E histone cluster 1, H3e 1.63 down 0.001210 0.0001517 HIST1H3F histone cluster 1, H3f 3.86 down 0.000031 0.0000002 HIST1H3H histone cluster 1, H3h 3.95 down 0.000014 0.0000000 HIST1H3J histone cluster 1, H3j 3.14 down 0.000177 0.0000062 HIST1H4A histone cluster 1, H4a 3.03 down 0.000042 0.0000004 HIST1H4B histone cluster 1, H4b 2.14 down 0.000078 0.0000013 HIST1H4C histone cluster 1, H4c 2.02 down 0.000600 0.0000518 HIST1H4D histone cluster 1, H4d 2.81 down 0.000106 0.0000024 HIST1H4E histone cluster 1, H4e 3.04 down 0.000097 0.0000019 HIST1H4F histone cluster 1, H4f 2.40 down 0.000246 0.0000112 HIST1H4H histone cluster 1, H4h 2.93 down 0.000243 0.0000109 HIST1H4I histone cluster 1, H4i 2.74 down 0.000075 0.0000013 HIST1H4J histone cluster 1, H4j 2.35 down 0.000053 0.0000006 HIST1H4K histone cluster 1, H4k 2.56 down 0.000043 0.0000004 HIST1H4L histone cluster 1, H4l 2.99 down 0.000582 0.0000496 HIST2H2AB histone cluster 2, H2ab 2.30 down 0.000028 0.0000001 HIST2H2AC histone cluster 2, H2ac 3.05 down 0.000179 0.0000063 HIST2H2BE histone cluster 2, H2be 2.50 down 0.002202 0.0003586 HIST2H2BF histone cluster 2, H2bf 2.22 down 0.000102 0.0000021 HIST2H3A histone cluster 2, H3a 3.55 down 0.000022 0.0000001 HIST2H4B histone cluster 2, H4b 2.42 down 0.000820 0.0000833 HIST3H2BB histone cluster 3, H2bb 3.02 down 0.000732 0.0000699 HMGB3 high mobility group box 3 1.74 down 0.003251 0.0006218 HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase 1.77 down 0.000234 0.0000103 HMMR hyaluronan-mediated motility receptor (RHAMM) 2.63 down 0.000046 0.0000005 HNRNPA1 heterogeneous nuclear ribonucleoprotein A1 2.06 down 0.000117 0.0000030 HNRNPA1L2 heterogeneous nuclear ribonucleoprotein A1-like 2 2.30 down 0.000064 0.0000010 HNRNPA2B1 heterogeneous nuclear ribonucleoprotein A2/B1 1.53 down 0.001623 0.0002336 HNRNPC heterogeneous nuclear ribonucleoprotein C (C1/C2) 1.80 down 0.000148 0.0000045 heterogeneous nuclear ribonucleoprotein D (AU-rich element HNRNPD 1.60 down 0.000593 0.0000510 RNA binding protein 1, 37kDa) HNRNPH3 heterogeneous nuclear ribonucleoprotein H3 (2H9) 1.92 down 0.000027 0.0000001 HNRNPK heterogeneous nuclear ribonucleoprotein K 1.54 down 0.002838 0.0005144 HNRNPLL heterogeneous nuclear ribonucleoprotein L-like 1.84 down 0.000116 0.0000029 heterogeneous nuclear ribonucleoprotein U (scaffold HNRNPU 1.91 down 0.000287 0.0000150 attachment factor A) HOXC4 homeobox C4 3.00 down 0.000452 0.0000320 HP1BP3 heterochromatin protein 1, binding protein 3 1.70 down 0.000490 0.0000373 HSD17B8 hydroxysteroid (17-beta) dehydrogenase 8 2.10 down 0.000211 0.0000086 HSPA4 heat shock 70kDa protein 4 1.65 down 0.000437 0.0000301 HSPA8 heat shock 70kDa protein 8 1.91 down 0.000250 0.0000115 HSPE1 heat shock 10kDa protein 1 1.52 down 0.000398 0.0000257 HSPH1 heat shock 105kDa/110kDa protein 1 1.99 down 0.000278 0.0000141 HTATIP2 HIV-1 Tat interactive protein 2, 30kDa 1.81 down 0.003166 0.0005996 HYLS1 hydrolethalus syndrome 1 1.64 down 0.001977 0.0003110 IAPP islet amyloid polypeptide 1.76 down 0.000068 0.0000010 ICAM5 intercellular adhesion molecule 5, telencephalin 1.55 down 0.000623 0.0000548 IDE insulin-degrading enzyme 1.51 down 0.000743 0.0000721 IER5L immediate early response 5-like 3.20 down 0.000060 0.0000008 IFT140 intraflagellar transport 140 homolog (Chlamydomonas) 2.40 down 0.003325 0.0006458 IFT74 intraflagellar transport 74 homolog (Chlamydomonas) 1.67 down 0.003474 0.0006825 IFT81 intraflagellar transport 81 homolog (Chlamydomonas) 1.62 down 0.000364 0.0000226 IL17B interleukin 17B 1.55 down 0.002939 0.0005380 IL1R1 interleukin 1 receptor, type I 2.01 down 0.001708 0.0002523 ILF3-AS1 ILF3 antisense RNA 1 (head to head) 1.73 down 0.000227 0.0000097 ILKAP integrin-linked kinase-associated serine/threonine phosphatase 1.56 down 0.001676 0.0002454 IMPA2 inositol(myo)-1(or 4)-monophosphatase 2 1.92 down 0.003082 0.0005768 IMPACT impact RWD domain protein 1.76 down 0.001296 0.0001682 ING3 inhibitor of growth family, member 3 2.52 down 0.001226 0.0001545 INO80 INO80 complex subunit 1.57 down 0.001052 0.0001232 INPP5A inositol polyphosphate-5-phosphatase, 40kDa 2.13 down 0.000159 0.0000050 INSIG1 insulin induced gene 1 1.83 down 0.000842 0.0000863 IPO11 importin 11 1.64 down 0.000586 0.0000501 IPO4 importin 4 1.51 down 0.000983 0.0001116 IQCE IQ motif containing E 1.68 down 0.001919 0.0002986 ISOC2 isochorismatase domain containing 2 1.51 down 0.002988 0.0005519 ITCH itchy E3 ubiquitin protein ligase 1.75 down 0.001436 0.0001966 KAT5 K(lysine) acetyltransferase 5 1.54 down 0.000087 0.0000016 KAZALD1 Kazal-type serine peptidase inhibitor domain 1 2.33 down 0.000266 0.0000131 KCNJ14 potassium inwardly-rectifying channel, subfamily J, member 14 2.03 down 0.000487 0.0000367 potassium voltage-gated channel, KQT-like subfamily, member KCNQ1 4.41 down 0.000147 0.0000045 1 KCNRG potassium channel regulator 2.21 down 0.001719 0.0002545 KCTD15 potassium channel tetramerization domain containing 15 1.95 down 0.000359 0.0000218 KIAA0020 KIAA0020 1.69 down 0.000294 0.0000157 KIAA0368 KIAA0368 1.56 down 0.001362 0.0001806 KIAA1024 KIAA1024 1.55 down 0.001952 0.0003061 KIAA1033 KIAA1033 1.76 down 0.000074 0.0000012 KIF14 kinesin family member 14 1.94 down 0.000021 0.0000001 KIF15 kinesin family member 15 1.57 down 0.003565 0.0007095 KIF18A kinesin family member 18A 1.87 down 0.000324 0.0000185 KIF20A kinesin family member 20A 1.90 down 0.000061 0.0000009 KIF20B kinesin family member 20B 1.89 down 0.000428 0.0000289 KLF10 Kruppel-like factor 10 1.53 down 0.002861 0.0005205 KLHL29 kelch-like family member 29 1.56 down 0.000147 0.0000045 KNSTRN kinetochore-localized astrin/SPAG5 binding protein 2.13 down 0.000069 0.0000011 KNTC1 kinetochore associated 1 1.62 down 0.000298 0.0000161 KTN1-AS1 KTN1 antisense RNA 1 2.42 down 0.000170 0.0000058 L3MBTL3 l(3)mbt-like 3 (Drosophila) 2.34 down 0.001006 0.0001155 LARP1B La ribonucleoprotein domain family, member 1B 1.74 down 0.002217 0.0003617 LARP4 La ribonucleoprotein domain family, member 4 1.57 down 0.000691 0.0000641 LARS leucyl-tRNA synthetase 2.02 down 0.000120 0.0000032 LBR lamin B receptor 1.63 down 0.002538 0.0004381 LEAP2 liver expressed antimicrobial peptide 2 3.05 down 0.000868 0.0000915 LENG9 leukocyte receptor cluster (LRC) member 9 2.52 down 0.000250 0.0000115 LFNG O-fucosylpeptide 3-beta-N- LFNG 2.39 down 0.000276 0.0000139 acetylglucosaminyltransferase phospholysine phosphohistidine inorganic pyrophosphate LHPP 2.06 down 0.000157 0.0000049 phosphatase LIAS lipoic acid synthetase 1.62 down 0.001142 0.0001392 LIG3 ligase III, DNA, ATP-dependent 1.69 down 0.003530 0.0006990 LINC00115 long intergenic non-protein coding RNA 115 2.58 down 0.003882 0.0007940 LINC00263 long intergenic non-protein coding RNA 263 1.96 down 0.001298 0.0001690 LINC00482 long intergenic non-protein coding RNA 482 1.58 down 0.000318 0.0000179 LINC01003 long intergenic non-protein coding RNA 1003 2.70 down 0.001698 0.0002496 LINC01004 long intergenic non-protein coding RNA 1004 1.83 down 0.002931 0.0005358 LINC01089 long intergenic non-protein coding RNA 1089 1.89 down 0.001704 0.0002512 LINC01315 long intergenic non-protein coding RNA 1315 1.53 down 0.000353 0.0000214 LIPT2 lipoyl(octanoyl) transferase 2 (putative) 1.85 down 0.001056 0.0001240 LMNB1 1.58 down 0.000023 0.0000001 LNP1 leukemia NUP98 fusion partner 1 2.90 down 0.001657 0.0002406 LOC100233156 tektin 4 pseudogene 2.86 down 0.000289 0.0000152 LOC93622 Morf4 family associated protein 1-like 1 pseudogene 1.65 down 0.000291 0.0000154 LONP1 lon peptidase 1, mitochondrial 1.51 down 0.001026 0.0001186 low density lipoprotein receptor-related protein 8, LRP8 1.56 down 0.001638 0.0002367 apolipoprotein e receptor LRPPRC leucine-rich pentatricopeptide repeat containing 1.63 down 0.001303 0.0001700 LRRC20 leucine rich repeat containing 20 1.64 down 0.000027 0.0000001 LRRC61 leucine rich repeat containing 61 1.52 down 0.004179 0.0008882 LRRCC1 leucine rich repeat and coiled-coil centrosomal protein 1 2.03 down 0.000197 0.0000076 LRRN2 leucine rich repeat neuronal 2 1.76 down 0.000144 0.0000043 leucine rich transmembrane and O-methyltransferase domain LRTOMT 1.57 down 0.001363 0.0001811 containing LSS lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase) 1.83 down 0.002023 0.0003203 LTV1 LTV1 ribosome biogenesis factor 1.51 down 0.000059 0.0000007 LUC7L3 LUC7-like 3 (S. cerevisiae) 3.27 down 0.004842 0.0010922 LYPLAL1 lysophospholipase-like 1 1.60 down 0.000343 0.0000205 LYRM4 LYR motif containing 4 1.51 down 0.003595 0.0007173 LZTFL1 leucine zipper transcription factor-like 1 1.73 down 0.003098 0.0005828 MAD1L1 MAD1 mitotic arrest deficient-like 1 (yeast) 1.77 down 0.000713 0.0000670 MALL mal, T-cell differentiation protein-like 1.80 down 0.000329 0.0000192 MAP4 microtubule-associated protein 4 1.85 down 0.000389 0.0000248 MARS methionyl-tRNA synthetase 1.66 down 0.000737 0.0000707 MAT2A methionine adenosyltransferase II, alpha 1.58 down 0.000121 0.0000032 MBLAC2 metallo-beta-lactamase domain containing 2 2.12 down 0.000027 0.0000001 MCM7 minichromosome maintenance complex component 7 1.76 down 0.000364 0.0000224 MDC1 mediator of DNA-damage checkpoint 1 1.53 down 0.000185 0.0000067 MED22 mediator complex subunit 22 1.74 down 0.001333 0.0001751 METAP2 methionyl aminopeptidase 2 2.09 down 0.000102 0.0000022 METTL10 methyltransferase like 10 1.55 down 0.000678 0.0000625 METTL12 methyltransferase like 12 2.42 down 0.000178 0.0000062 METTL16 methyltransferase like 16 1.72 down 0.000648 0.0000586 METTL25 methyltransferase like 25 1.99 down 0.001402 0.0001895 METTL3 methyltransferase like 3 2.12 down 0.000294 0.0000158 METTL4 methyltransferase like 4 1.52 down 0.000669 0.0000613 MFSD3 major facilitator superfamily domain containing 3 1.70 down 0.000435 0.0000298 MINA MYC induced nuclear antigen 1.58 down 0.003290 0.0006357 MIPEP mitochondrial intermediate peptidase 1.62 down 0.000195 0.0000074 MIR4697HG MIR4697 host gene (non-protein coding) 1.52 down 0.003773 0.0007639 MIRLET7BHG MIRLET7B host gene (non-protein coding) 2.45 down 0.000794 0.0000797 MIS18BP1 MIS18 binding protein 1 1.57 down 0.003143 0.0005928 MKX mohawk homeobox 3.22 down 0.004296 0.0009258 myeloid/lymphoid or mixed-lineage leukemia (trithorax MLLT10 1.51 down 0.000149 0.0000046 homolog, Drosophila); translocated to, 10 myeloid/lymphoid or mixed-lineage leukemia (trithorax MLLT6 1.56 down 0.000894 0.0000957 homolog, Drosophila); translocated to, 6 MMP11 matrix metallopeptidase 11 (stromelysin 3) 1.93 down 0.000289 0.0000151 MNX1-AS1 MNX1 antisense RNA 1 (head to head) 1.71 down 0.002084 0.0003339 MORN1 MORN repeat containing 1 2.72 down 0.000253 0.0000119 MOS v-mos Moloney murine sarcoma viral oncogene homolog 2.06 down 0.001835 0.0002808 membrane protein, palmitoylated 7 (MAGUK p55 subfamily MPP7 1.66 down 0.000446 0.0000311 member 7) mitochondrial rRNA methyltransferase 1 homolog (S. MRM1 1.73 down 0.000582 0.0000495 cerevisiae) MRPS25 mitochondrial ribosomal protein S25 2.44 down 0.000180 0.0000064 MRPS31 mitochondrial ribosomal protein S31 1.70 down 0.000533 0.0000431 MRTO4 mRNA turnover 4 homolog (S. cerevisiae) 1.76 down 0.002521 0.0004336 MSTO1 misato 1, mitochondrial distribution and morphology regulator 2.02 down 0.000124 0.0000033 MTA1 metastasis associated 1 2.04 down 0.000638 0.0000569 MTAP methylthioadenosine phosphorylase 1.81 down 0.000915 0.0000992 MTFMT mitochondrial methionyl-tRNA formyltransferase 1.51 down 0.000222 0.0000094 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) MTHFD1L 1.61 down 0.000550 0.0000454 1-like MTL5 metallothionein-like 5, testis-specific (tesmin) 2.51 down 0.000269 0.0000134 MTR 5-methyltetrahydrofolate- methyltransferase 1.77 down 0.002690 0.0004763 MXRA7 matrix-remodelling associated 7 1.58 down 0.002344 0.0003897 MYC v-myc avian myelocytomatosis viral oncogene homolog 1.69 down 0.001174 0.0001449 v-myc avian myelocytomatosis viral oncogene lung carcinoma MYCL 1.79 down 0.000459 0.0000332 derived homolog MYCNOS MYCN opposite strand 1.58 down 0.000295 0.0000159 MYO5C myosin VC 1.84 down 0.000113 0.0000027 N4BP1 NEDD4 binding protein 1 1.55 down 0.000169 0.0000058 NAA15 N(alpha)-acetyltransferase 15, NatA auxiliary subunit 2.20 down 0.002703 0.0004790 NADK NAD kinase 1.65 down 0.000253 0.0000120 NAMPT nicotinamide phosphoribosyltransferase 1.82 down 0.002378 0.0003983 NARS2 asparaginyl-tRNA synthetase 2, mitochondrial (putative) 1.93 down 0.000364 0.0000225 NASP nuclear autoantigenic sperm protein (histone-binding) 1.53 down 0.000306 0.0000168 NDE1 nudE neurodevelopment protein 1 1.87 down 0.000149 0.0000046 NECAB3 N-terminal EF-hand calcium binding protein 3 1.53 down 0.000740 0.0000710 nuclear factor of activated T-cells, cytoplasmic, - NFATC1 2.01 down 0.000371 0.0000231 dependent 1 nuclear factor of activated T-cells, cytoplasmic, calcineurin- NFATC2IP 1.61 down 0.000512 0.0000405 dependent 2 interacting protein NFYA nuclear transcription factor Y, alpha 1.74 down 0.000751 0.0000733 NFYB nuclear transcription factor Y, beta 1.87 down 0.000020 0.0000000 NIN ninein (GSK3B interacting protein) 1.89 down 0.001382 0.0001853 NKRF NFKB repressing factor 1.81 down 0.000008 0.0000000 NKX2-5 NK2 homeobox 5 1.52 down 0.004179 0.0008892 NLE1 notchless homolog 1 (Drosophila) 2.33 down 0.001273 0.0001642 NLRP2 NLR family, pyrin domain containing 2 1.63 down 0.000389 0.0000250 NMD3 NMD3 ribosome export adaptor 1.69 down 0.000290 0.0000153 NOC3L nucleolar complex associated 3 homolog (S. cerevisiae) 2.05 down 0.000027 0.0000001 NOL10 nucleolar protein 10 1.95 down 0.000640 0.0000573 NOL9 nucleolar protein 9 1.52 down 0.000061 0.0000008 NOP16 NOP16 nucleolar protein 1.52 down 0.000222 0.0000094 NOP56 NOP56 ribonucleoprotein 1.65 down 0.000458 0.0000330 NOP58 NOP58 ribonucleoprotein 1.68 down 0.000134 0.0000038 NPRL3 nitrogen permease regulator-like 3 (S. cerevisiae) 1.95 down 0.001129 0.0001367 NPTN neuroplastin 1.54 down 0.002314 0.0003833 NR2F1-AS1 NR2F1 antisense RNA 1 1.58 down 0.003486 0.0006862 NR6A1 nuclear receptor subfamily 6, group A, member 1 1.80 down 0.000775 0.0000771 NREP neuronal regeneration related protein 1.53 down 0.004048 0.0008483 NSMCE2 non-SMC element 2, MMS21 homolog (S. cerevisiae) 1.71 down 0.000963 0.0001083 NSUN2 NOP2/Sun RNA methyltransferase family, member 2 1.76 down 0.000098 0.0000020 NT5M 5',3'-nucleotidase, mitochondrial 2.01 down 0.000220 0.0000093 NTHL1 nth endonuclease III-like 1 (E. coli) 1.77 down 0.000429 0.0000290 NTSR1 neurotensin receptor 1 (high affinity) 2.75 down 0.000061 0.0000009 NUDT18 nudix (nucleoside diphosphate linked moiety X)-type motif 18 1.66 down 0.000691 0.0000642 nuclear fragile X mental retardation protein interacting protein NUFIP1 2.36 down 0.000477 0.0000353 1 nuclear fragile X mental retardation protein interacting protein NUFIP2 1.56 down 0.000630 0.0000557 2 NUP133 nucleoporin 133kDa 1.62 down 0.004418 0.0009617 NUP35 nucleoporin 35kDa 1.58 down 0.001883 0.0002915 NUP98 nucleoporin 98kDa 1.70 down 0.001451 0.0001991 OARD1 O-acyl-ADP-ribose deacylase 1 2.17 down 0.000060 0.0000008 OBSL1 -like 1 1.54 down 0.003484 0.0006853 ODF3B outer dense fiber of sperm tails 3B 2.05 down 0.000321 0.0000183 OLA1 Obg-like ATPase 1 2.36 down 0.000753 0.0000736 OPA1 optic atrophy 1 (autosomal dominant) 1.53 down 0.001445 0.0001981 OR51B5 olfactory receptor, family 51, subfamily B, member 5 3.45 down 0.000061 0.0000009 ORC2 origin recognition complex, subunit 2 1.56 down 0.001045 0.0001219 OSBPL1A oxysterol binding protein-like 1A 1.91 down 0.000061 0.0000008 OSBPL5 oxysterol binding protein-like 5 1.67 down 0.002152 0.0003480 OSGEPL1 O-sialoglycoprotein endopeptidase-like 1 2.35 down 0.000613 0.0000532 OTUD6B OTU domain containing 6B 1.93 down 0.000771 0.0000763 PACS2 phosphofurin acidic cluster sorting protein 2 3.17 down 0.000539 0.0000439 platelet-activating factor acetylhydrolase 1b, regulatory subunit PAFAH1B1 2.05 down 0.000426 0.0000287 1 (45kDa) PAFAH2 platelet-activating factor acetylhydrolase 2, 40kDa 1.51 down 0.003907 0.0008043 PAIP1 poly(A) binding protein interacting protein 1 1.70 down 0.001402 0.0001897 PALD1 phosphatase domain containing, paladin 1 1.70 down 0.000086 0.0000016 PARPBP PARP1 binding protein 1.58 down 0.001809 0.0002749 PARVB parvin, beta 2.66 down 0.000070 0.0000011 PCF11 PCF11 cleavage and factor subunit 2.56 down 0.000022 0.0000001 PCK2 phosphoenolpyruvate carboxykinase 2 (mitochondrial) 2.04 down 0.001122 0.0001356 PCM1 pericentriolar material 1 1.75 down 0.001805 0.0002736 PCSK1N proprotein convertase subtilisin/kexin type 1 inhibitor 1.57 down 0.000723 0.0000687 PCSK6 proprotein convertase subtilisin/kexin type 6 1.96 down 0.002168 0.0003512 PCSK9 proprotein convertase subtilisin/kexin type 9 1.54 down 0.000198 0.0000076 PDCD6IP programmed cell death 6 interacting protein 1.81 down 0.001513 0.0002120 PDE3B phosphodiesterase 3B, cGMP-inhibited 1.66 down 0.001120 0.0001351 PDE9A phosphodiesterase 9A 1.79 down 0.000452 0.0000320 PDK1 pyruvate dehydrogenase kinase, isozyme 1 1.72 down 0.000773 0.0000766 PDP1 pyruvate dehyrogenase phosphatase catalytic subunit 1 1.66 down 0.000426 0.0000286 PDS5, regulator of cohesion maintenance, homolog A (S. PDS5A 1.77 down 0.000109 0.0000026 cerevisiae) PDS5, regulator of cohesion maintenance, homolog B (S. PDS5B 2.84 down 0.000056 0.0000007 cerevisiae) PECR peroxisomal trans-2-enoyl-CoA reductase 1.54 down 0.000737 0.0000706 PEMT phosphatidylethanolamine N-methyltransferase 1.62 down 0.000967 0.0001089 PGLS 6-phosphogluconolactonase 1.77 down 0.000108 0.0000025 PHF19 PHD finger protein 19 1.65 down 0.000304 0.0000167 PHOSPHO2 phosphatase, orphan 2 1.68 down 0.003252 0.0006224 PIF1 PIF1 5'-to-3' DNA helicase 4.26 down 0.000044 0.0000004 PIH1D1 PIH1 domain containing 1 1.55 down 0.000323 0.0000184 PINX1 PIN2/TERF1 interacting, telomerase inhibitor 1 1.84 down 0.002210 0.0003602 PITPNA phosphatidylinositol transfer protein, alpha 1.58 down 0.000049 0.0000005 PKD1 polycystic kidney disease 1 (autosomal dominant) 1.53 down 0.000528 0.0000422 PLAC1 placenta-specific 1 1.76 down 0.001871 0.0002885 PLAGL2 pleiomorphic adenoma gene-like 2 1.59 down 0.001204 0.0001504 PLCB2 phospholipase C, beta 2 1.74 down 0.000591 0.0000508 PLCH1 phospholipase C, eta 1 2.34 down 0.002990 0.0005528 PLEKHJ1 pleckstrin homology domain containing, family J member 1 1.79 down 0.003663 0.0007348 polo-like kinase 1 3.04 down 0.000206 0.0000082 PLK4 polo-like kinase 4 1.92 down 0.001131 0.0001374 PLXNA1 plexin A1 1.57 down 0.003927 0.0008100 PMM2 phosphomannomutase 2 1.73 down 0.000171 0.0000059 PMS1 PMS1 postmeiotic segregation increased 1 (S. cerevisiae) 1.65 down 0.000390 0.0000251 PNN pinin, desmosome associated protein 2.15 down 0.002552 0.0004417 PNPT1 polyribonucleotide 1 1.55 down 0.001853 0.0002843 POLR1B polymerase (RNA) I polypeptide B, 128kDa 2.11 down 0.004667 0.0010406 POLR3G polymerase (RNA) III (DNA directed) polypeptide G (32kD) 1.81 down 0.003154 0.0005964 POLR3H polymerase (RNA) III (DNA directed) polypeptide H (22.9kD) 1.57 down 0.000867 0.0000913 PP7080 uncharacterized LOC25845 1.87 down 0.000132 0.0000037 peroxisome proliferator-activated receptor gamma, coactivator PPARGC1B 1.73 down 0.003267 0.0006299 1 beta protein tyrosine phosphatase, receptor type, f polypeptide PPFIA3 1.55 down 0.000162 0.0000052 (PTPRF), interacting protein (liprin), alpha 3 PPHLN1 periphilin 1 1.95 down 0.001156 0.0001416 PPIEL peptidylprolyl isomerase E-like pseudogene 1.70 down 0.000765 0.0000755 PPIL6 peptidylprolyl isomerase (cyclophilin)-like 6 1.56 down 0.000288 0.0000151 PPIP5K1 diphosphoinositol pentakisphosphate kinase 1 1.76 down 0.001810 0.0002754 PPP2R3C protein phosphatase 2, regulatory subunit B'', gamma 1.55 down 0.004107 0.0008657 PPP3CB protein phosphatase 3, catalytic subunit, beta isozyme 1.77 down 0.002555 0.0004424 PPP6C protein phosphatase 6, catalytic subunit 2.65 down 0.000538 0.0000438 PPP6R2 protein phosphatase 6, regulatory subunit 2 1.86 down 0.000209 0.0000085 PPP6R3 protein phosphatase 6, regulatory subunit 3 1.97 down 0.000068 0.0000010 PRDM16 PR domain containing 16 2.40 down 0.000289 0.0000151 PRELID2 PRELI domain containing 2 1.52 down 0.001501 0.0002091 PRKAA1 protein kinase, AMP-activated, alpha 1 catalytic subunit 1.72 down 0.003099 0.0005830 PRKACB protein kinase, cAMP-dependent, catalytic, beta 3.82 down 0.000079 0.0000014 PRKAG1 protein kinase, AMP-activated, gamma 1 non-catalytic subunit 2.04 down 0.000165 0.0000054 PRKCDBP protein kinase C, delta binding protein 1.86 down 0.000800 0.0000805 PRMT3 protein arginine methyltransferase 3 2.08 down 0.000015 0.0000000 PRMT6 protein arginine methyltransferase 6 1.69 down 0.000014 0.0000000 PRMT7 protein arginine methyltransferase 7 1.65 down 0.001225 0.0001542 PRPF38B pre-mRNA processing factor 38B 1.75 down 0.001298 0.0001690 PRPF4B pre-mRNA processing factor 4B 1.61 down 0.003727 0.0007518 PRR22 proline rich 22 2.59 down 0.000073 0.0000012 PRRC2B proline-rich coiled-coil 2B 1.53 down 0.000917 0.0000996 PSKH1 protein serine kinase H1 2.93 down 0.000197 0.0000075 PSMG4 proteasome (prosome, macropain) assembly chaperone 4 1.93 down 0.002484 0.0004241 PSRC1 proline/serine-rich coiled-coil 1 2.17 down 0.000458 0.0000329 PTCD3 pentatricopeptide repeat domain 3 1.76 down 0.003153 0.0005959 PTK2 protein tyrosine kinase 2 1.65 down 0.000329 0.0000191 PTP4A3 protein tyrosine phosphatase type IVA, member 3 1.81 down 0.002756 0.0004928 PTPLAD1 protein tyrosine phosphatase-like A domain containing 1 1.53 down 0.004630 0.0010279 PTTG2 pituitary tumor-transforming 2 1.57 down 0.001420 0.0001932 PUS1 pseudouridylate synthase 1 1.57 down 0.002623 0.0004602 PUS7 pseudouridylate synthase 7 (putative) 2.03 down 0.000655 0.0000592 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B) 1.75 down 0.000390 0.0000251 PVRL3 poliovirus receptor-related 3 1.73 down 0.001661 0.0002416 PWP1 PWP1 homolog (S. cerevisiae) 1.58 down 0.002049 0.0003251 PYCR1 pyrroline-5-carboxylate reductase 1 1.93 down 0.003262 0.0006281 PYCRL pyrroline-5-carboxylate reductase-like 1.82 down 0.000061 0.0000009 PYROXD1 pyridine nucleotide-disulphide oxidoreductase domain 1 1.89 down 0.000460 0.0000333 R3HDM2 R3H domain containing 2 1.73 down 0.000192 0.0000072 RAB11A RAB11A, member RAS oncogene family 1.53 down 0.001465 0.0002015 RAB11FIP4 RAB11 family interacting protein 4 (class II) 2.56 down 0.000191 0.0000071 RAB26 RAB26, member RAS oncogene family 1.94 down 0.000569 0.0000479 RABGAP1L RAB GTPase activating protein 1-like 2.06 down 0.002483 0.0004236 RABL2A RAB, member of RAS oncogene family-like 2A 1.53 down 0.000533 0.0000431 RACGAP1 Rac GTPase activating protein 1 1.59 down 0.000159 0.0000051 RAD50 RAD50 homolog (S. cerevisiae) 1.64 down 0.000022 0.0000001 RALGPS1 Ral GEF with PH domain and SH3 binding motif 1 1.56 down 0.002462 0.0004177 RANBP2 RAN binding protein 2 1.73 down 0.002107 0.0003386 RARS2 arginyl-tRNA synthetase 2, mitochondrial 1.60 down 0.000220 0.0000093 RBBP4 retinoblastoma binding protein 4 1.57 down 0.002917 0.0005323 RBM12 RNA binding motif protein 12 2.59 down 0.000123 0.0000033 RCC2 regulator of chromosome condensation 2 1.64 down 0.001508 0.0002107 RDM1 RAD52 motif containing 1 1.62 down 0.002640 0.0004641 REEP5 receptor accessory protein 5 1.58 down 0.000959 0.0001078 RET ret proto-oncogene 2.07 down 0.003714 0.0007490 RHOBTB1 Rho-related BTB domain containing 1 1.63 down 0.001402 0.0001897 RHOBTB3 Rho-related BTB domain containing 3 1.58 down 0.000390 0.0000251 RMDN2 regulator of microtubule dynamics 2 1.56 down 0.004490 0.0009836 RNA5-8S5 RNA, 5.8S ribosomal 5 1.85 down 0.003397 0.0006637 RNF141 ring finger protein 141 1.84 down 0.000255 0.0000122 RNF145 ring finger protein 145 1.58 down 0.000437 0.0000301 RNF207 ring finger protein 207 1.53 down 0.000971 0.0001096 RNF213 ring finger protein 213 1.74 down 0.000776 0.0000773 RNF216 ring finger protein 216 1.58 down 0.000956 0.0001068 RNF222 ring finger protein 222 1.57 down 0.004695 0.0010492 ROCK2 Rho-associated, coiled-coil containing protein kinase 2 1.82 down 0.001023 0.0001180 RPL10A ribosomal protein L10a 2.26 down 0.002988 0.0005512 RPL22L1 ribosomal protein L22-like 1 6.99 down 0.000259 0.0000125 RPL3 ribosomal protein L3 2.10 down 0.001269 0.0001631 RPL37 ribosomal protein L37 1.62 down 0.002118 0.0003410 RPP25L /MRP 25kDa subunit-like 1.57 down 0.001470 0.0002028 RPRD1A regulation of nuclear pre-mRNA domain containing 1A 2.16 down 0.000598 0.0000515 RPS14 ribosomal protein S14 2.36 down 0.000125 0.0000034 RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1 2.12 down 0.000060 0.0000008 RPUSD3 RNA pseudouridylate synthase domain containing 3 1.76 down 0.000548 0.0000451 RPUSD4 RNA pseudouridylate synthase domain containing 4 2.50 down 0.000044 0.0000004 RRP15 ribosomal RNA processing 15 homolog (S. cerevisiae) 1.57 down 0.001153 0.0001411 ribosomal RNA processing 9, small subunit (SSU) processome RRP9 1.59 down 0.000408 0.0000268 component, homolog (yeast) RRS1 RRS1 ribosome biogenesis regulator homolog (S. cerevisiae) 1.53 down 0.000823 0.0000836 RSC1A1 regulatory solute carrier protein, family 1, member 1 1.53 down 0.004090 0.0008596 RSPH3 radial spoke 3 homolog (Chlamydomonas) 1.58 down 0.000539 0.0000440 RTDR1 rhabdoid tumor deletion region gene 1 2.68 down 0.002600 0.0004536 S100PBP S100P binding protein 1.62 down 0.001528 0.0002150 SAPCD2 suppressor APC domain containing 2 1.80 down 0.000093 0.0000018 SBNO1 strawberry notch homolog 1 (Drosophila) 2.27 down 0.000083 0.0000015 SCAMP1 secretory carrier membrane protein 1 1.90 down 0.001546 0.0002185 SCARA3 scavenger receptor class A, member 3 1.89 down 0.000454 0.0000324 SCARNA13 small Cajal body-specific RNA 13 6.16 down 0.000010 0.0000000 SCARNA17 small Cajal body-specific RNA 17 1.97 down 0.004563 0.0010065 SCARNA9 small Cajal body-specific RNA 9 1.93 down 0.001066 0.0001256 SCD stearoyl-CoA desaturase (delta-9-desaturase) 1.85 down 0.000426 0.0000286 SCLY selenocysteine lyase 1.58 down 0.000325 0.0000186 SDAD1 SDA1 domain containing 1 1.68 down 0.000150 0.0000046 SEC11A SEC11 homolog A (S. cerevisiae) 1.51 down 0.000255 0.0000122 SEC23A Sec23 homolog A (S. cerevisiae) 1.69 down 0.002107 0.0003384 SEC23IP SEC23 interacting protein 1.62 down 0.000907 0.0000977 SEC24A SEC24 family member A 1.51 down 0.003253 0.0006239 SEC63 SEC63 homolog (S. cerevisiae) 1.98 down 0.004309 0.0009294 SECISBP2 SECIS binding protein 2 1.86 down 0.000079 0.0000014 SEPT10 septin 10 1.50 down 0.003513 0.0006948 SERBP1 SERPINE1 mRNA binding protein 1 1.57 down 0.000528 0.0000422 SETD6 SET domain containing 6 1.69 down 0.001362 0.0001808 SFPQ splicing factor proline/glutamine-rich 1.52 down 0.001264 0.0001620 SGOL2 shugoshin-like 2 (S. pombe) 1.97 down 0.000488 0.0000369 SH3PXD2B SH3 and PX domains 2B 1.59 down 0.001276 0.0001646 SNF2 histone linker PHD RING helicase, E3 ubiquitin protein SHPRH 2.14 down 0.002070 0.0003312 ligase SIM2 single-minded family bHLH transcription factor 2 2.59 down 0.000247 0.0000113 SIRT5 sirtuin 5 1.77 down 0.002186 0.0003552 solute carrier family 11 (proton-coupled divalent metal ion SLC11A2 1.93 down 0.000722 0.0000685 transporter), member 2 SLC18B1 solute carrier family 18, subfamily B, member 1 1.97 down 0.000307 0.0000169 solute carrier family 25 (aspartate/glutamate carrier), member SLC25A13 1.90 down 0.000027 0.0000001 13 solute carrier family 25 (mitochondrial folate carrier), member SLC25A32 1.76 down 0.003090 0.0005800 32 solute carrier family 25 (mitochondrial iron transporter), SLC25A37 1.63 down 0.000234 0.0000103 member 37 solute carrier family 25 (mitochondrial carrier; adenine SLC25A6 1.82 down 0.000119 0.0000031 nucleotide translocator), member 6 SLC30A9 solute carrier family 30 (zinc transporter), member 9 1.91 down 0.000102 0.0000022 solute carrier family 35 (UDP-xylose/UDP-N- SLC35B4 2.28 down 0.000753 0.0000735 acetylglucosamine transporter), member B4 SLC35F5 solute carrier family 35, member F5 2.23 down 0.002175 0.0003529 SLC35G1 solute carrier family 35, member G1 2.14 down 0.001496 0.0002080 SLC38A1 solute carrier family 38, member 1 1.57 down 0.000135 0.0000039 SLC39A11 solute carrier family 39, member 11 1.64 down 0.000262 0.0000127 solute carrier family 5 (sodium/multivitamin and iodide SLC5A6 1.68 down 0.000044 0.0000004 cotransporter), member 6 SLC6A8 solute carrier family 6 (neurotransmitter transporter), member 8 1.53 down 0.001495 0.0002077 solute carrier family 6 (neurotransmitter transporter, ), SLC6A9 1.67 down 0.000786 0.0000787 member 9 solute carrier family 7 (anionic transporter light SLC7A11 1.56 down 0.004947 0.0011250 chain, xc- system), member 11 solute carrier family 7 (cationic amino acid transporter, y+ SLC7A2 2.78 down 0.000017 0.0000000 system), member 2 solute carrier family 9, subfamily A (NHE8, cation proton SLC9A8 1.72 down 0.002062 0.0003288 antiporter 8), member 8 structural maintenance of flexible hinge domain SMCHD1 1.82 down 0.000710 0.0000667 containing 1 SMIM19 small integral membrane protein 19 2.15 down 0.000044 0.0000004 SNHG1 small nucleolar RNA host gene 1 (non-protein coding) 1.56 down 0.000488 0.0000370 SNHG10 small nucleolar RNA host gene 10 (non-protein coding) 2.19 down 0.000878 0.0000931 SNHG12 small nucleolar RNA host gene 12 (non-protein coding) 1.59 down 0.002471 0.0004209 SNHG15 small nucleolar RNA host gene 15 (non-protein coding) 1.57 down 0.000454 0.0000324 SNHG17 small nucleolar RNA host gene 17 (non-protein coding) 1.66 down 0.000450 0.0000317 SNHG20 small nucleolar RNA host gene 20 (non-protein coding) 1.68 down 0.004499 0.0009873 SNHG3 small nucleolar RNA host gene 3 (non-protein coding) 1.71 down 0.000219 0.0000091 SNHG7 small nucleolar RNA host gene 7 (non-protein coding) 2.55 down 0.001195 0.0001482 SOBP sine oculis binding protein homolog (Drosophila) 1.59 down 0.000272 0.0000136 SON SON DNA binding protein 2.37 down 0.000250 0.0000116 SORD sorbitol dehydrogenase 1.94 down 0.002062 0.0003283 SOX4 SRY (sex determining region Y)-box 4 2.13 down 0.000282 0.0000146 SPEF2 sperm flagellar 2 3.17 down 0.001002 0.0001149 SPEN spen family transcriptional repressor 1.67 down 0.004254 0.0009115 SPTLC2 serine palmitoyltransferase, long chain base subunit 2 2.16 down 0.000027 0.0000001 SRBD1 S1 RNA binding domain 1 1.94 down 0.000263 0.0000128 SREBF1 sterol regulatory element binding transcription factor 1 1.73 down 0.001741 0.0002595 SRGAP3 SLIT-ROBO Rho GTPase activating protein 3 1.50 down 0.000656 0.0000594 SRPK1 SRSF protein kinase 1 1.65 down 0.000624 0.0000550 SRSF1 serine/arginine-rich splicing factor 1 2.39 down 0.000915 0.0000991 SRSF3 serine/arginine-rich splicing factor 3 1.65 down 0.001493 0.0002069 SRSF5 serine/arginine-rich splicing factor 5 1.56 down 0.002733 0.0004862 SSU72 RNA polymerase II CTD phosphatase homolog (S. SSU72 1.93 down 0.002750 0.0004909 cerevisiae) suppression of tumorigenicity 13 (colon carcinoma) (Hsp70 ST13 1.54 down 0.000074 0.0000012 interacting protein) ST3GAL3 ST3 beta-galactoside alpha-2,3-sialyltransferase 3 2.05 down 0.000413 0.0000273 ST3GAL6 ST3 beta-galactoside alpha-2,3-sialyltransferase 6 1.94 down 0.000014 0.0000000 ST6GAL1 ST6 beta-galactosamide alpha-2,6-sialyltranferase 1 1.86 down 0.000051 0.0000006 STAG3 stromal antigen 3 1.52 down 0.003846 0.0007830 STARD8 StAR-related lipid transfer (START) domain containing 8 2.69 down 0.000174 0.0000060 STK33 serine/threonine kinase 33 1.68 down 0.000463 0.0000336 STOX1 storkhead box 1 1.74 down 0.003784 0.0007662 STRADB STE20-related kinase adaptor beta 1.85 down 0.000386 0.0000246 SUGP2 SURP and G patch domain containing 2 1.58 down 0.001511 0.0002115 SURF6 surfeit 6 1.96 down 0.000301 0.0000164 SYNCRIP synaptotagmin binding, cytoplasmic RNA interacting protein 1.65 down 0.000276 0.0000139 TACC3 transforming, acidic coiled-coil containing protein 3 1.51 down 0.001078 0.0001278 TAF1 RNA polymerase II, TATA box binding protein (TBP)- TAF1 1.59 down 0.000163 0.0000053 associated factor, 250kDa TAF12 RNA polymerase II, TATA box binding protein (TBP)- TAF12 1.77 down 0.000081 0.0000014 associated factor, 20kDa TAF15 RNA polymerase II, TATA box binding protein (TBP)- TAF15 2.26 down 0.000062 0.0000009 associated factor, 68kDa TAF4b RNA polymerase II, TATA box binding protein (TBP)- TAF4B 1.84 down 0.000850 0.0000878 associated factor, 105kDa TARDBP TAR DNA binding protein 3.42 down 0.000512 0.0000404 TBC1D20 TBC1 domain family, member 20 1.64 down 0.001440 0.0001972 TBC1D22A TBC1 domain family, member 22A 1.81 down 0.000263 0.0000128 TBC1D22B TBC1 domain family, member 22B 1.53 down 0.001493 0.0002069 TBC1D31 TBC1 domain family, member 31 1.50 down 0.002127 0.0003429 TBCD tubulin folding D 1.52 down 0.000438 0.0000302 TBL3 transducin (beta)-like 3 1.88 down 0.000047 0.0000005 TCF7L2 transcription factor 7-like 2 (T-cell specific, HMG-box) 1.89 down 0.001009 0.0001161 TCFL5 transcription factor-like 5 (basic helix-loop-helix) 2.41 down 0.000014 0.0000000 TECPR2 tectonin beta-propeller repeat containing 2 1.57 down 0.000368 0.0000229 TEKT4 tektin 4 2.99 down 0.000325 0.0000186 TESPA1 thymocyte expressed, positive selection associated 1 1.52 down 0.001741 0.0002591 TEX10 testis expressed 10 1.54 down 0.000109 0.0000026 TEX19 testis expressed 19 1.86 down 0.000677 0.0000624 TFRC transferrin receptor 1.65 down 0.000030 0.0000002 TGIF1 TGFB-induced factor homeobox 1 1.63 down 0.001111 0.0001336 THEM4 thioesterase superfamily member 4 1.92 down 0.000124 0.0000033 THEM6 thioesterase superfamily member 6 2.38 down 0.000195 0.0000074 THNSL1 -like 1 (S. cerevisiae) 2.01 down 0.000472 0.0000346 THOC2 THO complex 2 1.67 down 0.000851 0.0000886 TIA1 TIA1 cytotoxic granule-associated RNA binding protein 2.07 down 0.003256 0.0006260 of inner mitochondrial membrane 23 homolog B TIMM23B 1.89 down 0.004225 0.0009041 (yeast) TLE6 transducin-like enhancer of split 6 1.58 down 0.001781 0.0002684 TM4SF18 transmembrane 4 L six family member 18 2.64 down 0.000282 0.0000145 TMBIM4 transmembrane BAX inhibitor motif containing 4 2.77 down 0.001298 0.0001688 TMEM129 transmembrane protein 129 2.56 down 0.000197 0.0000075 TMEM17 transmembrane protein 17 1.61 down 0.001124 0.0001358 TMEM181 transmembrane protein 181 1.64 down 0.000846 0.0000873 TMEM187 transmembrane protein 187 2.07 down 0.000283 0.0000146 TMEM248 transmembrane protein 248 1.93 down 0.000006 0.0000000 TMEM67 transmembrane protein 67 1.73 down 0.001094 0.0001305 TMX2 thioredoxin-related transmembrane protein 2 1.65 down 0.000184 0.0000067 TNFAIP8L1 tumor necrosis factor, alpha-induced protein 8-like 1 1.57 down 0.002345 0.0003901 TNFRSF13C tumor necrosis factor receptor superfamily, member 13C 1.57 down 0.000294 0.0000157 TNFRSF18 tumor necrosis factor receptor superfamily, member 18 1.51 down 0.000497 0.0000382 TOLLIP-AS1 TOLLIP antisense RNA 1 (head to head) 2.19 down 0.000695 0.0000648 TRA2B transformer 2 beta homolog (Drosophila) 1.70 down 0.001336 0.0001758 TRAPPC12 trafficking protein particle complex 12 1.83 down 0.000127 0.0000035 TRAPPC9 trafficking protein particle complex 9 1.60 down 0.000071 0.0000011 TRDMT1 tRNA aspartic acid methyltransferase 1 1.79 down 0.000108 0.0000026 TRIM33 tripartite motif containing 33 1.97 down 0.000626 0.0000553 TRIM65 tripartite motif containing 65 1.80 down 0.000449 0.0000316 TRMT10A tRNA methyltransferase 10 homolog A (S. cerevisiae) 2.00 down 0.000179 0.0000063 TRMT10C tRNA methyltransferase 10 homolog C (S. cerevisiae) 1.55 down 0.000022 0.0000001 TRMT61A tRNA methyltransferase 61 homolog A (S. cerevisiae) 1.84 down 0.000770 0.0000761 TRMT61B tRNA methyltransferase 61 homolog B (S. cerevisiae) 1.87 down 0.000783 0.0000781 TSEN2 TSEN2 tRNA splicing endonuclease subunit 2.22 down 0.001278 0.0001651 thiosulfate sulfurtransferase (rhodanese)-like domain TSTD3 1.50 down 0.000045 0.0000004 containing 3 TTC12 tetratricopeptide repeat domain 12 1.94 down 0.000417 0.0000278 TTC27 tetratricopeptide repeat domain 27 1.67 down 0.001069 0.0001262 TTC7A tetratricopeptide repeat domain 7A 1.55 down 0.001656 0.0002404 TTF2 transcription termination factor, RNA polymerase II 1.50 down 0.000226 0.0000097 TTLL1 tubulin tyrosine ligase-like family, member 1 1.99 down 0.000199 0.0000076 TUBB4B tubulin, beta 4B class IVb 1.54 down 0.000621 0.0000543 TUBE1 tubulin, epsilon 1 1.55 down 0.000425 0.0000285 TUBGCP5 tubulin, gamma complex associated protein 5 1.51 down 0.003411 0.0006670 TUG1 taurine up-regulated 1 (non-protein coding) 1.93 down 0.000922 0.0001006 TULP4 tubby like protein 4 1.84 down 0.000147 0.0000045 TXNDC11 thioredoxin domain containing 11 1.74 down 0.000872 0.0000921 U2SURP U2 snRNP-associated SURP domain containing 2.30 down 0.000633 0.0000562 UBA6 ubiquitin-like modifier activating enzyme 6 2.31 down 0.001432 0.0001956 UBAP2L ubiquitin associated protein 2-like 2.96 down 0.000803 0.0000810 UBASH3B ubiquitin associated and SH3 domain containing B 1.94 down 0.000436 0.0000299 UBE2E1 ubiquitin-conjugating enzyme E2E 1 1.67 down 0.003068 0.0005737 UBE3B ubiquitin protein ligase E3B 1.96 down 0.001109 0.0001329 UBE3D ubiquitin protein ligase E3D 1.59 down 0.000512 0.0000404 UBE4B ubiquitination factor E4B 1.58 down 0.000204 0.0000080 UBP1 upstream binding protein 1 (LBP-1a) 1.73 down 0.001019 0.0001172 UBQLN4 ubiquilin 4 1.78 down 0.000899 0.0000966 UFSP1 UFM1-specific peptidase 1 (non-functional) 1.54 down 0.003085 0.0005781 UNC5A unc-5 homolog A (C. elegans) 1.95 down 0.001788 0.0002699 URB1 URB1 ribosome biogenesis 1 homolog (S. cerevisiae) 1.91 down 0.000917 0.0000998 UROS uroporphyrinogen III synthase 1.75 down 0.000412 0.0000271 USP10 ubiquitin specific peptidase 10 1.76 down 0.001823 0.0002785 USP13 ubiquitin specific peptidase 13 (isopeptidase T-3) 1.82 down 0.002255 0.0003701 USP25 ubiquitin specific peptidase 25 3.19 down 0.000166 0.0000055 USP40 ubiquitin specific peptidase 40 2.04 down 0.000459 0.0000332 USP47 ubiquitin specific peptidase 47 1.59 down 0.001733 0.0002577 USP7 ubiquitin specific peptidase 7 (herpes virus-associated) 1.69 down 0.000389 0.0000249 UTP15, U3 small nucleolar ribonucleoprotein, homolog (S. UTP15 1.72 down 0.000949 0.0001055 cerevisiae) UTP20, small subunit (SSU) processome component, homolog UTP20 2.07 down 0.000081 0.0000015 (yeast) VAC14 Vac14 homolog (S. cerevisiae) 1.80 down 0.000167 0.0000056 VAMP (vesicle-associated membrane protein)-associated VAPA 3.66 down 0.002586 0.0004501 protein A, 33kDa VAMP (vesicle-associated membrane protein)-associated VAPB 2.05 down 0.002345 0.0003903 protein B and C VPS9D1-AS1 VPS9D1 antisense RNA 1 1.57 down 0.003773 0.0007634 VTI1A vesicle transport through interaction with t-SNAREs 1A 2.22 down 0.000586 0.0000501 VWA8 von Willebrand factor A domain containing 8 2.54 down 0.000723 0.0000686 WAPAL wings apart-like homolog (Drosophila) 1.52 down 0.000716 0.0000677 WDR12 WD repeat domain 12 1.66 down 0.000992 0.0001132 WDR35 WD repeat domain 35 2.33 down 0.000917 0.0000998 WDR36 WD repeat domain 36 1.73 down 0.000321 0.0000182 WDR43 WD repeat domain 43 1.50 down 0.001126 0.0001361 WDR70 WD repeat domain 70 1.91 down 0.000079 0.0000014 WDR78 WD repeat domain 78 2.62 down 0.000257 0.0000124 WHSC1 Wolf-Hirschhorn syndrome candidate 1 1.79 down 0.000487 0.0000367 WWC3 WWC family member 3 1.86 down 0.000424 0.0000284 WWP2 WW domain containing E3 ubiquitin protein ligase 2 1.59 down 0.002635 0.0004628 XXYLT1 xyloside xylosyltransferase 1 2.05 down 0.000165 0.0000054 YARS tyrosyl-tRNA synthetase 1.55 down 0.004255 0.0009121 YLPM1 YLP motif containing 1 1.69 down 0.002439 0.0004129 YPEL4 yippee-like 4 (Drosophila) 1.66 down 0.001437 0.0001967 YTHDC2 YTH domain containing 2 1.94 down 0.000453 0.0000322 ZBED4 zinc finger, BED-type containing 4 1.62 down 0.000250 0.0000116 ZBTB2 zinc finger and BTB domain containing 2 1.67 down 0.000786 0.0000786 ZCCHC8 zinc finger, CCHC domain containing 8 1.50 down 0.000496 0.0000381 ZCWPW1 zinc finger, CW type with PWWP domain 1 1.52 down 0.004179 0.0008876 ZDHHC3 zinc finger, DHHC-type containing 3 2.00 down 0.000450 0.0000317 ZFC3H1 zinc finger, C3H1-type containing 2.28 down 0.000180 0.0000064 ZFYVE28 zinc finger, FYVE domain containing 28 1.67 down 0.003512 0.0006941 ZMYM2 zinc finger, MYM-type 2 1.62 down 0.002421 0.0004089 ZMYM4 zinc finger, MYM-type 4 1.52 down 0.000028 0.0000001 ZNF215 zinc finger protein 215 1.81 down 0.000169 0.0000057 ZNF280D zinc finger protein 280D 1.63 down 0.003628 0.0007259 ZNF302 zinc finger protein 302 1.88 down 0.001259 0.0001607 ZNF469 zinc finger protein 469 1.74 down 0.000484 0.0000364 ZNF485 zinc finger protein 485 1.64 down 0.000831 0.0000846 ZNF497 zinc finger protein 497 2.09 down 0.000338 0.0000200 ZNF581 zinc finger protein 581 1.84 down 0.000086 0.0000016 ZNF706 zinc finger protein 706 1.71 down 0.000168 0.0000057 ZNF775 zinc finger protein 775 1.62 down 0.001198 0.0001488 ZNF789 zinc finger protein 789 1.98 down 0.000929 0.0001020 ZNRF1 zinc and ring finger 1, E3 ubiquitin protein ligase 2.20 down 0.000205 0.0000080

Supplementary Table 2. Redox-related, FUra-responsive genes as determined by cDNA microarray analysis

Microarray data from Supplemental Table 1 were queried with regard to the GO and KEGG databases (see text) to identify genes involved in redox metabolism. The fold change represents the extent of induction by exposure to 10 µM FUra for 24 h. The p-value is corrected for multiple testing using the Benjamini- Hochberg algorithm (see Materials and Methods).

Gene Fold Corrected Description Regulation p-value Symbol Change p-value AKR1B10 aldo-keto reductase family 1, member B10 (aldose reductase) (AKR1B10), mRNA [NM_020299] 6.37 up 0.000054 0.000001 AKR1B15 aldo-keto reductase family 1, member B15 (AKR1B15), mRNA [NM_001080538] 6.04 up 0.000259 0.000012 aldo-keto reductase family 1, member C1 (dihydrodiol dehydrogenase 1; 20-alpha (3-alpha)- 2.31 up AKR1C1 hydroxysteroid dehydrogenase) (AKR1C1), mRNA [NM_001353] 0.001859 0.000286 aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II) 1.91 up AKR1C3 (AKR1C3), mRNA [NM_003739] 0.001267 0.000163 aldehyde dehydrogenase 3 family, member A1 (ALDH3A1), transcript variant 1, mRNA 2.02 up ALDH3A1 [NM_001135168] 0.001249 0.000159 aldehyde dehydrogenase 4 family, member A1 (ALDH4A1), nuclear gene encoding mitochondrial 2.56 up ALDH4A1 protein, transcript variant P5CDhS, mRNA [NM_170726] 0.000558 0.000046 BLVRB biliverdin reductase B (flavin reductase (NADPH)) (BLVRB), mRNA [NM_000713] 2.01 up 0.001495 0.000208 CBR3 carbonyl reductase 3 (CBR3), mRNA [NM_001236] 1.89 up 0.003410 0.000667 CYB5R1 cytochrome b5 reductase 1 (CYB5R1), mRNA [NM_016243] 1.66 up 0.002679 0.000473 DHRS13 dehydrogenase/reductase (SDR family) member 13 (DHRS13), mRNA [NM_144683] 1.87 up 0.001244 0.000158 DHRS7 dehydrogenase/reductase (SDR family) member 7 (DHRS7), mRNA [NM_016029] 1.59 up 0.000098 0.000002 ferredoxin reductase (FDXR), nuclear gene encoding mitochondrial protein, transcript variant 2, 2.27 up FDXR mRNA [NM_004110] 0.000178 0.000006 GLRX glutaredoxin (thioltransferase) (GLRX), transcript variant 1, mRNA [NM_002064] 1.54 up 0.000476 0.000035 GLRX2 glutaredoxin 2 (GLRX2), transcript variant 1, mRNA [NM_016066] 1.68 up 0.000623 0.000055 GPX1 glutathione peroxidase 1 (GPX1), transcript variant 2, mRNA [NM_201397] 1.65 up 0.000812 0.000082 hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7 (HSD3B7), 1.66 up HSD3B7 transcript variant 2, mRNA [NM_001142777] 0.000698 0.000065 KDSR 3-ketodihydrosphingosine reductase (KDSR), mRNA [NM_002035] 1.72 up 0.000967 0.000109 LOXL2 lysyl oxidase-like 2 (LOXL2), mRNA [NM_002318] 1.59 up 0.000106 0.000002 LOXL4 lysyl oxidase-like 4 (LOXL4), mRNA [NM_032211] 2.04 up 0.000887 0.000095 NADPH dependent diflavin oxidoreductase 1 (NDOR1), transcript variant 1, mRNA 1.84 up NDOR1 [NM_001144026] 0.000445 0.000031 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 11, 17.3kDa (NDUFB11), nuclear gene 1.54 up NDUFB11 encoding mitochondrial protein, transcript variant 1, mRNA [NM_019056] 0.000022 0.000000 proline dehydrogenase (oxidase) 1 (PRODH), nuclear gene encoding mitochondrial protein, 1.95 up PRODH transcript variant 1, mRNA [NM_016335] 0.000208 0.000008 RRM1 ribonucleotide reductase M1 (RRM1), mRNA [NM_001033] 1.54 up 0.000884 0.000094 superoxide dismutase 2, mitochondrial (SOD2), nuclear gene encoding mitochondrial protein, 1.56 up SOD2 transcript variant 2, mRNA [NM_001024465] 0.000307 0.000017 sulfide quinone reductase-like (yeast) (SQRDL), nuclear gene encoding mitochondrial protein, 1.54 up SQRDL mRNA [NM_021199] 0.000185 0.000007 TP53I3 tumor protein p53 inducible protein 3 (TP53I3), transcript variant 1, mRNA [NM_004881] 4.78 up 0.000041 0.000000 TXNDC17 thioredoxin domain containing 17 (TXNDC17), mRNA [NM_032731] 1.61 up 0.000740 0.000071

acyl-CoA dehydrogenase family, member 9 (ACAD9), nuclear gene encoding mitochondrial 1.58 down ACAD9 protein, transcript variant 1, mRNA [NM_014049] 0.003176 0.000603 acyl-CoA dehydrogenase, C-2 to C-3 short chain (ACADS), nuclear gene encoding mitochondrial 1.64 down ACADS protein, mRNA [NM_000017] 0.004722 0.001056 acyl-Coenzyme A dehydrogenase, short/branched chain (ACADSB), nuclear gene encoding 2.01 down ACADSB mitochondrial protein, mRNA [NM_001609] 0.000376 0.000023 ALKBH3 alkB, alkylation repair homolog 3 (E. coli) (ALKBH3), mRNA [NM_139178] 1.55 down 0.001059 0.000125 AOC3 amine oxidase, copper containing 3 (vascular adhesion protein 1) (AOC3), mRNA [NM_003734] 1.64 down 0.001775 0.000267 branched chain keto acid dehydrogenase E1, beta polypeptide (BCKDHB), nuclear gene encoding 1.54 down BCKDHB mitochondrial protein, transcript variant 2, mRNA [NM_000056] 0.003890 0.000798 choline dehydrogenase (CHDH), nuclear gene encoding mitochondrial protein, mRNA 1.83 down CHDH [NM_018397] 0.000694 0.000065 CPOX coproporphyrinogen oxidase (CPOX), mRNA [NM_000097] 1.64 down 0.001790 0.000270 CRYL1 crystallin, lambda 1 (CRYL1), mRNA [NM_015974] 1.96 down 0.000274 0.000014 CRYZ crystallin, zeta (quinone reductase) (CRYZ), transcript variant 1, mRNA [NM_001130042] 1.68 down 0.000543 0.000044 CYB5RL cytochrome b5 reductase-like (CYB5RL), mRNA [NM_001031672] 2.30 down 0.000351 0.000021 dehydrogenase/reductase (SDR family) member 2 (DHRS2), transcript variant 1, mRNA 2.94 down DHRS2 [NM_182908] 0.000022 0.000000 DHRS3 dehydrogenase/reductase (SDR family) member 3 (DHRS3), mRNA [NM_004753] 1.61 down 0.000253 0.000012 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), transcript variant 1, mRNA 1.77 down HMGCR [NM_000859] 0.000234 0.000010 HSD17B8 hydroxysteroid (17-beta) dehydrogenase 8 (HSD17B8), mRNA [NM_014234] 2.10 down 0.000211 0.000009 HTATIP2 HIV-1 Tat interactive protein 2, 30kDa (HTATIP2), transcript variant 2, mRNA [NM_006410] 1.81 down 0.003166 0.000600 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L), nuclear gene 1.53 down MTHFD1L encoding mitochondrial protein, mRNA [NM_015440] 0.000167 0.000006 pyruvate dehydrogenase kinase, isozyme 1 (PDK1), nuclear gene encoding mitochondrial protein, 1.72 down PDK1 mRNA [NM_002610] 0.000773 0.000077 pyruvate dehyrogenase phosphatase catalytic subunit 1 (PDP1), nuclear gene encoding 1.66 down PDP1 mitochondrial protein, transcript variant 2, mRNA [NM_001161779] 0.000426 0.000029 PECR peroxisomal trans-2-enoyl-CoA reductase (PECR), mRNA [NM_018441] 1.54 down 0.000737 0.000071 PYCR1 pyrroline-5-carboxylate reductase 1 (PYCR1), transcript variant 1, mRNA [NM_006907] 1.84 down 0.001594 0.000228 PYCRL pyrroline-5-carboxylate reductase-like (PYCRL), mRNA [NM_023078] 1.82 down 0.000061 0.000001 PYROXD1 pyridine nucleotide-disulphide oxidoreductase domain 1 (PYROXD1), mRNA [NM_024854] 1.89 down 0.000460 0.000033 SORD sorbitol dehydrogenase (SORD), mRNA [NM_003104] 1.94 down 0.002062 0.000328 TMX2 thioredoxin-related transmembrane protein 2 (TMX2), transcript variant 1, mRNA [NM_015959] 1.63 down 0.000286 0.000015 TXNDC11 thioredoxin domain containing 11 (TXNDC11), mRNA [NM_015914] 1.74 down 0.000872 0.000092