Genome-Wide DNA Methylation Profiling Identifies Differential Methylation in Uninvolved Psoriatic Epidermis Deepti Verma, Anna-Karin Ekman, Cecilia Bivik Eding and Charlotta Enerbäck

The self-archived postprint version of this journal article is available at Linköping University Institutional Repository (DiVA): http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-147791

N.B.: When citing this work, cite the original publication. Verma, D., Ekman, A., Bivik Eding, C., Enerbäck, C., (2018), Genome-Wide DNA Methylation Profiling Identifies Differential Methylation in Uninvolved Psoriatic Epidermis, Journal of Investigative Dermatology, 138(5), 1088-1093. https://doi.org/10.1016/j.jid.2017.11.036

Original publication available at: https://doi.org/10.1016/j.jid.2017.11.036 Copyright: Elsevier http://www.elsevier.com/

Genome-Wide DNA Methylation Profiling Identifies Differential Methylation in Uninvolved Psoriatic Epidermis

Deepti Verma*a, Anna-Karin Ekman*a, Cecilia Bivik Edinga and Charlotta Enerbäcka

*Authors contributed equally

aIngrid Asp Psoriasis Research Center, Department of Clinical and Experimental Medicine,

Division of Dermatology, Linköping University, Linköping, Sweden

Corresponding author:

Charlotta Enerbäck Ingrid Asp Psoriasis Research Center, Department of Clinical and Experimental Medicine, Linköping University SE-581 85 Linköping, Sweden Phone: +46 10 103 7429 E-mail: [email protected] Short title Differential methylation in psoriasis Abbreviations CGI, CpG island; DMS, differentially methylated site; RRBS, reduced representation bisulphite sequencing

Keywords (max 6) psoriasis, epidermis, methylation, Wnt, susceptibility, expression

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ABSTRACT

Psoriasis is a chronic inflammatory skin disease with both local and systemic components.

Genome-wide approaches have identified more than 60 psoriasis-susceptibility loci, but genes

are estimated to explain only one third of the heritability in psoriasis, suggesting additional, yet unidentified, sources of heritability. Epigenetic modifications have been linked to psoriasis and altered DNA methylation patterns in psoriatic versus healthy skin have been reported in whole-

skin biopsies. In this study, focusing on epigenetic modifications in the psoriatic uninvolved

skin, we compared the lesional and non-lesional epidermis from psoriasis patients with epidermis from healthy controls. We performed an exhaustive genome-wide DNA methylation profiling using reduced representation bisulfite sequencing, which interrogates the methylation status of ~3-4 million CpG sites. More than two thousand strongly differentially methylated sites (DMS) were identified and a striking overrepresentation of the Wnt and cadherin pathways among the DMS was found. In particular, we observe a strong differential methylation in several psoriasis candidate genes. A substantial number of DMS present in the uninvolved vs healthy epidermis suggests the presence of a pre psoriatic state in the clinically healthy skin type. Our exploratory study represents a starting point for identifying biomarkers for psoriasis-prone skin before disease onset.

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INTRODUCTION

The genetic component in psoriasis pathogenesis is well recognized, and genome-wide

association studies (GWAS) have identified more than 60 psoriasis-susceptibility loci

(Ellinghaus et al., 2010, Nair et al., 2009, Tang et al., 2014, Tsoi et al., 2012). However, it is

estimated that the identified genes explain only 28% of the heritability of psoriasis, suggesting

additional, yet unidentified, sources of heritability (Tsoi et al., 2015).

The incomplete concordance in disease status between monozygotic twins suggests a role for

environmental factors in psoriasis pathogenesis (Das et al., 2009). Environmental triggers, such

as infections, stress, injuries, smoking, alcohol and lithium medication, can induce an auto-

inflammatory response mediated by DNA methylation in genetically predisposed individuals

(Baker et al., 1997, Tsankov et al., 2000). Since parental exposure to environmental triggers has been shown to affect the transgenerational transmission of altered DNA methylation

(Trerotola et al., 2015), epigenetics may contribute to the missing heritability in psoriasis.

The aim of this study was to investigate the epigenetic regulation underlying psoriasis susceptibility. Previous studies using Illumina’s 27-450K resolution have shown aberrant DNA methylation in psoriatic lesional (PP) when compared with non-lesional (PN) or healthy skin

(NN) (Gu et al., 2015, Roberson et al., 2012, Zhou et al., 2016). Using whole-biopsy samples,

Roberson et al. detected intermediate methylation of uninvolved skin and found 15 differentially methylated sites between PN/NN. However, an in-depth comparison of methylation differences between PN and NN skin is lacking. We performed an extensive investigation of the methylome in PP, PN and NN epidermis covering three-four million CpG residues. We report more than 2,000 strongly differentially methylated sites (DMS), thereby clearly distinguishing the skin phenotypes. Substantial methylation differences between non-

3 lesional and healthy epidermis, involving the Wnt and cadherin pathways, is to our knowledge previously unreported.

RESULTS

Global DNA methylation profiling of PP, PN and NN epidermis

Using reduced representation bisulphite sequencing (RRBS) to map the global CpG methylation state, we obtained ~21-52 million total reads in the samples, with a mean value of

35,899,496 per sample. The mapping efficiency ranged from 48-59%, with an average of

19,060,737 sites successfully aligning back to the human genome (UCSC hg19) and the read depth ranged from six to nine fold. The technical validation of RRBS data using pyrosequencing showed highly consistent results for all the tested sites (data not shown). Using flow cytometry, the CD45+ leukocyte population was found to contribute less than 2.4% of the total cells (data not shown).

The number of covered CpG sites and DMS are shown in Table 1. The genomic distribution of these sites are represented in Supplementary Figures 1a-d.

The top 2,000 DMS showing greater than 33% differential methylation in the pairwise comparisons, demonstrated several overrepresented pathways relevant for psoriasis

(Supplementary Table 1). Using a significant threshold of a Bonferroni-adjusted p-value of

-9 0.05, we found common enrichments of pathways like cadherin (PN/NN PBonferroni = 2.8x10 ,

-21 -9 -7 PP/PN PBonferroni = 8.5x10 , PP/NN PBonferroni= 6.2x 10 ) and Wnt (PN/NN PBonferroni = 2.8x10 ,

-20 -10 PP/PN PBonferroni = 2x10 , PP/NN P Bonferroni = 3.5x10 ). The pathways exclusively detected in the lesional skin when compared with the non-lesional or healthy skin were heterotrimeric G-

-3 -2 protein signaling (PP/PN PBonferroni =1.19x10 , PP/NN PBonferroni = 1.13x10 ) and inflammation

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-2 mediated through cytokines and chemokines (PP/PN PBonferroni = 3.6 x10 , PP/NN PBonferroni =

2.9 x10-2), which might reflect accelerated cell growth and sustained inflammation.

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The CpG methylation pattern in the psoriasis-susceptible and the lesional epidermis

compared with the normal epidermis

The PN/NN comparison revealed a substantial number of DMS (Figure 1a). The DMS

overlapping between the PN/NN and PP/NN comparisons likely represent a methylation

pattern that is intrinsic to the psoriatic skin, rather than resulting from the inflammatory process

(Figure 1b, Supplemental data S1). The overlapping genes show an overrepresentation of the

-6 -8 Wnt and cadherin pathways (P Bonferroni = 3.1x10 and 4x 10 , respectively). Using the recent

Reactome resource in PANTHER (Mi et al., 2017) we found that these genes were enriched in

-2 non-canonical Wnt signaling (PBonferroni = 2 x10 ). The Wnt-pathway regulating genes including Wnt7B, NFATc1, CELSR2 and FZD7 demonstrated >33% differential methylation at multiple sites. FZD7, the Frizzled receptor for Wnt proteins, is differentially expressed in psoriasis (Gudjonsson et al., 2010). IL23R, which has a strong pathogenic association with

psoriasis (Harden et al., 2015), was hypermethylated in both the PN/NN and PP/NN.

The CpG methylation pattern in the psoriasis-susceptible and the normal epidermis compared with the psoriatic lesion

The overlap between the PN and NN epidermis (Figure 1b) when compared with PP likely represents a methylation pattern induced by the inflammatory or disease-related state. The genes overlapping between the PP/NN and PP/PN (Supplemental Data S1) displayed

-10 prominent overrepresentations of the cadherin (PBonferroni = 3.2x10 ) and Wnt pathways

-7 (PBonferroni = 1.9x10 ). In addition, overrepresentations of the heterotrimeric G-protein

-2 signaling Gq alpha- and Go alpha- mediated pathway (PBonferroni = 1.4x10 ) and the integrin

-4 pathway (PBonferroni = 7.8 x10 ) were found. The overlapping cadherin and Wnt genes were

-10 enriched for non-canonical Wnt signaling (PBonferroni = 5x10 ) and Ca2+ pathways (PBonferroni

= 3x10-9). Calcium is a key second messenger in the non-canonical Wnt signaling (Kohn and

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Moon, 2005). Furthermore, SFRP4, a negative regulator of Wnt signaling, Wnt5A and its receptor FZD2 were found to be differentially methylated.

The > 33% hypermethylated genes included DUSP1 and EXPH5, which presented at several sites in the PP/PN and PP/NN. The hypermethylation of DUSP1, a negative regulator of p38 mitogen-activated protein kinase activity, was in accordance with its reported downregulation in psoriasis (Kjellerup et al., 2013). EXPH5 is a GTPase effector protein and is implicated in inherited skin fragility disease (McGrath et al., 2012). A known susceptibility locus for psoriasis, GJB2, was found to be > 33% hypomethylated at several sites, which is in accordance with its reported upregulation in psoriasis (Sun et al., 2010).

To exclude the universally expressed genes, we made use of the Body Index of human Gene

Expression (BIGE) database (Gerber et al., 2013), which includes 687 skin-associated genes

(SAGs). Upon intersecting our methylation data with the SAGs, we found 340 common

matches for the PP/NN and 223 common matches for the PN/NN comparison (Supplemental

data S2 & S3). GO analysis revealed the considerable enrichment of terms related to

desmosome organization, keratinocyte proliferation and skin-barrier function (Figure 1c),

suggesting a role for methylation in the regulation of a substantial number of skin-specific

genes.

Methylation levels distinguish involved, uninvolved and normal epidermis To determine whether the PN and NN can be distinguished based on the differences in

methylation pattern, we selected the 100 most DMS between the PP and NN comparisons. We

performed an unsupervised hierarchical clustering, including the PN samples, which revealed

a distinct clustering between the PP, NN and PP (Figure 2a). The PN samples, albeit in a distinct cluster, displayed a methylation pattern that more closely resembled the NN than the PP epidermis.

Altered methylation at the psoriasis risk-associated loci

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Two recent meta-analysis identified 59 replicated psoriasis risk-associated genes (Tsoi et al.,

2015, Tsoi et al., 2017. The genes are listed in the Supplemental data S4). We investigated the

level of DNA methylation for all the CpG sites in these psoriasis risk-associated genes, including their promoters. Using a permutation test, we found 38 sites with >33% DMS among

the psoriasis candidate genes, which was greater than expected by chance (P < 0.01). These

sites mainly annotated to the candidate genes TRAF3IP2, ZMIZ1 and CARD14. The number of such DMS in the top 15 cis-acting eQTLs in psoriatic lesional skin (Ding et al., 2010) was not

found to be greater than expected by chance (P = 0.92).

Transcriptomic profiling of epidermis

We found a distinct differential gene expression in the PP/PN (496 differentially expressed

genes) and PP/NN comparisons (587 differentially expressed genes). The hallmark genes

(IL36G, KYNU, RHCG, ATP12A, HPSE, CCL20, SERPINB13, SOX7 and C20orF24), universally shown to be upregulated in psoriatic full-thickness skin (Swindell et al., 2014), displayed an increased expression in our epidermal samples from the PP/NN and PP/PN comparisons.

An unsupervised hierarchical clustering of the top differentially expressed sites resulted in the

absence of clustering between the PN and the NN samples, indicating that the expression

differences between them are subtle (Figure 2b).

Association of mRNA expression with methylation levels in the epidermis Using a differential methylation cut-off of 33%, we found 44 shared genes in the PP/NN and

41 shared genes in the PP/PN. The genes DUSP1 and GATA3, both previously shown to be

downregulated in psoriasis (Kjellerup et al., 2013, Racz et al., 2011), demonstrated several >

33% DMS, along with a corresponding transcriptional downregulation in the PP/NN

comparison. Additional genes with key skin-regulatory functions, where hypermethylation

correlated with a downregulated expression, included EXPH5, AHNAK, PTPN14, NR1D1 and

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PTPN21 (Gerber et al., 2013). Strongly hypomethylated genes with an upregulated transcription in the PP/NN comparison included FOXE1, GJB2, RAB31, WWOX, ATP1B1,

SLC7A5 and SOX7, all of which have been implicated in psoriasis (Suarez-Farinas et al., 2012).

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DISCUSSION We report a comprehensive genome-wide analysis using epidermal samples to study global

DNA methylation and RNA expression patterns in psoriasis. We utilized the next-generation sequencing-based technique RRBS to investigate DNA methylation in the epidermis derived from lesional and non-lesional psoriasis and from normal skin. The epidermis was removed using ammonium thiocyanate, a method that does not affect gene expression (Clemmensen et al., 2009). In order to minimize the confounding effects of cell heterogeneity, we specifically analyzed the epidermis rather than the full-thickness skin.

A few studies using the Illumina’s 27-450K resolution in full-thickness skin, have reported a difference in methylation between the PP skin and the PN or NN skin (Roberson et al., 2012,

Zhou et al., 2016). Using almost 10 times the number of probes, we now provide additional, comprehensive data, and validate the previous findings. Using the Illumina 27K, Roberson et al (Roberson et al., 2012) identified 1,108 differentially methylated genes, of which 443 were found in our pairwise PP/NN comparison. We also identified six (MANI1C1, SPIRE2, AHDC1,

DLGAP4, ECE1 and CYP2S1) of the nine differentially methylated loci recently described by

Zhou et al (Zhou et al., 2016). Several DMS mapped to the GWAS psoriasis-risk genes and altered methylation at multiple sites were observed for TRAF3IP2, ZMIZ1 and CARD14.

Substantial differential methylation was evident in the comparison of PN and NN. Intriguingly, these DMS included several sites (328 genes) identified by Roberson et al., as well as five of the nine sites described by Zhou et al. in the PP/NN comparisons, showing that the methylation differences not only delineate the lesional and healthy skin but also the clinically normal, uninvolved skin from the healthy skin. When comparing DMS present in both PP and PN compared with NN, a strong overrepresentation of differentially methylated Wnt and cadherin pathway genes was found, which were significantly enriched for the non-canonical Wnt/Ca2+ signaling. Wnt signaling plays critical roles in embryogenesis and tissue homeostasis. NFATc1,

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a WNT5A downstream gene implicated in non-canonical Wnt signaling, demonstrated DMS at

multiple sites. Interestingly, NFATc1 was recently shown to be important for imiquimod-

induced psoriasiform dermatitis by suppressing IL-10 in B cells (Alrefai et al., 2016).

When comparing the PP skin with the PN (or NN) skin, we attempted to filter out the changes

in methylation that are a consequence of the inflammatory reaction in lesional skin to

distinguish them from the changes that underlie disease susceptibility. An overrepresentation

of DMS associated with Wnt signaling was found and included SFRP4, a negative regulator of

Wnt signaling, which was recently shown to be downregulated in psoriasis through an

epigenetic mechanism (Bai et al., 2015). SFRP4 directly inhibited keratinocyte proliferation triggered by proinflammatory cytokines in vitro (Bai et al., 2015). Moreover, we found differential methylations of Wnt5A, as well as its receptor, FZD2. Wnt5a is an important pro- inflammatory factor that has been implicated in several inflammatory diseases, such as rheumatoid arthritis, atherosclerosis and psoriasis (Pashirzad et al., 2016). The expression of

Wnt5A is increased in psoriatic epidermis, together with its receptors, FZD2 and FZD5

(Gudjonsson et al., 2010, Reischl et al., 2007, Romanowska et al., 2009). Interestingly, Wnt5A is one of the very few genes that retain increased expression in resolving psoriatic lesions

(Suarez-Farinas et al., 2011).

As previously reported (Roberson et al., 2012, Zhang et al., 2013, Zhou et al., 2016), we found that relatively few, albeit functionally relevant, subsets of genes overlapped between methylation and expression. Unlike the clear distinction in the methylation pattern between the

PN and NN samples, the differences in gene expression between these groups were subtle. This suggests that DNA methylation does not directly translate into altered expression but may poise the associated genes for expression in response to future triggers.

The differences between PN and NN might be influenced by the underlying systemic/local inflammation or genetic factors. The increased inflammatory activity in PN skin was suggested

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by Johnson-Huang et al, who demonstrated infiltrating CD3+ T-cells, and inflammatory DCs

in PN skin in patients with psoriasis (Johnson-Huang et al., 2012). In favor of an intrinsic

abnormality in PN skin is our recent finding of an apoptosis-resistant phenotype in cultured uninvolved psoriatic skin. Interestingly, this effect persisted after several passages of culture

(Bivik Eding and Enerback, 2017). Moreover, uninvolved skin demonstrated abnormal barrier function and differential in vitro keratinocyte spreading (Chen et al., 2001, Ye et al., 2014).

In conclusion, we demonstrate substantial methylation differences between uninvolved psoriatic skin and healthy skin, suggesting that the uninvolved skin might represent a pre- psoriatic state. Further studies are required to identify the biological mechanisms underlying the altered methylation patterns in PN vs NN skin.

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MATERIAL AND METHODS

The detailed protocols and statistical analysis are described in Supplemental methods.

Study population and samples

Written informed consent was obtained from the patients and control subjects, and the ethical

principles of the Declaration of Helsinki were followed. The study was approved by the

Regional ethics committee in Linkoping. Skin punch biopsies (4 mm) were obtained from

psoriasis patients and controls. The psoriasis diagnosis had been confirmed by a dermatologist.

The participating patients were not receiving any systemic treatment, and the lesions from

which the skin biopsies were obtained were untreated. The PP biopsies were taken from the

lower back in an active psoriasis lesion and PN skin was obtained from a non-lesional area on

the lower back of the same patient at least 10 cm from the active, lesional skin. A total of 12

biopsies, six from psoriasis patients (including three pairwise PP and PN) and six NN biopsies,

were obtained. All participants were males, to avoid confounding gender-specific methylation

patterns (Liu et al., 2010). The epidermis was detached by soaking the biopsy in 3.8% sterile

ammonium thiocyanate in PBS for 30 minutes, as previously described (Clemmensen et al.,

2009). DNA was immediately isolated using the Blood and Tissue DNA extraction kit

(QIAGEN, Hilden, Germany).

Methylation analysis

The DNA samples were processed for genome-wide DNA methylation sequencing analysis by

Zymo Research (Irvine, CA) (Supplementary methods). The CpG sites having a minimum

read-depth of five and a methylation difference cut-off ±10%, were annotated into promoter, exon, intron or CpG island. The gene boundary was defined by RefSeq annotations for the human genome (UCSC hg19) and the promoter was defined as +/- 1 kb from the transcription

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start site of the gene. The methylation level of each sampled cytosine was estimated as the number of methylated cytosines divided by the total number of cytosines. Pairwise comparisons were done for PP/NN, PP/PN and PN/NN samples. The methylation difference for each site was calculated by subtracting the median methylation value of the sample of interest from the reference sample. For increased stringency, we based our analyses on the top

2,000 DMS with a differential methylation cut off of 33%.

Gene ontology (GO) annotation

The PANTHER (http://www.PANTHERdb.org/) database was used for the gene ontology and pathway overrepresentation analysis. Official gene symbols were used as input to calculate the statistical overrepresentation of biological process GO terms.

Gene expression profiling

Gene expression was determined using Affymetrix Beadchip 2.0 (Affymetrix, Santa Clara,

CA), following the manufacturer’s instructions. The differential expression of genes was

determined using the GeneSpring GX software (Agilent technologies, Santa Clara, CA), with a cut-off of ±1.5 f.c.

Statistics

The statistical significance of the methylation difference was determined by the Student’s t‐ test or the Fisher’s Exact Test. Statistical overrepresentation of PANTHER pathways was determined using a Bonferroni correction. The differential methylation of CpG sites in psoriasis candidate genes and eQTL loci were investigated using a permutation test.

Data Access

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The DNA methylation data have been deposited in the NCBI Gene Expression Omnibus database under accession number GSE 103038.

Conflict of interest The authors declare no conflict of interest

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TABLES

Table 1. Distribution of differentially methylated sites in the pairwise comparisons

PP vs NN PP vs PN PN vs NN Total sites 2,072,217 3,058,077 2,007,044 DMS 83,587 58,627 35,056 Hypomethylated 44,528 29,558 25,546 Strongly hypomethylated 5,364 2,762 1,644 Hypermethylated 39,059 29,069 9,511 Strongly hypermethylated 8,504 4,556 669 DMS: Differentially methylated sites

FIGURE LEGENDS

Figure 1. Differentially methylated sites in the pairwise comparisons. (a) Volcano plot showing the differentially methylated sites in the PN/NN comparison. Sites showing > ± 10% differential methylation are shown. Blue dots represent the strongly hyper/hypo-methylated sites > ± 33% (b) Venn

diagrams showing the number of overlapping hyper and hypo methylated annotated sites in the pairwise

comparisons PP/NN, PP/PN and PN/NN (c) Displays gene ontology (GO) enrichments of the top 10

GO terms obtained upon intersecting the differentially methylated genes in PN/NN and PP/NN with the

Skin-Associated Genes (SAG) database. PN, Uninvolved; NN, Healthy; PP, Involved

Figure 2. Differential methylation and gene expression profiles. (a) Heat map of the PP (N =3), NN

(N=6) and PN (N=3) samples. Methylation ratio values of the top 100 DMS that distinguish PP from

NN epidermis were used. Unsupervised hierarchical clustering, upon including the same sites from PN,

are shown. Red color indicates a hypomethylation and yellow color indicates a hypermethylation. (b)

Heat map of the normalized expression values of the top 50 differentially expressed genes that

distinguish PP from NN epidermis. Unsupervised hierarchical clustering, upon including the same sites

from PN, are shown. The yellow values indicate a relative increase, while the red values indicate a relative decrease in expression. PN, Uninvolved; NN, Healthy; PP, Involved

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Supplemental methods

Identification of epidermal cell populations by flow cytometry

The phenotyping of epidermal cells was performed using the Gallios flow cytometer. FITC- conjugated monoclonal mouse anti-human antibody against CD45 (clone HI30, BD

Bioscience, San Jose, CA) was used and the percentage of CD45+ cells was determined using

Kaluza software (Beckman Coulter, CA).

Methyl-MiniSeq™ library construction

Libraries were prepared from 200-500 ng of genomic DNA, digested with 60 units of TaqαI and 30 units of MspI (NEB) sequentially and then extracted with a Zymo Research (ZR) DNA

Clean & Concentrator™-5 kit. Fragments were ligated to pre-annealed adapters containing 5’- methyl-cytosine instead of cytosine, according to Illumina’s specified guidelines

(www.illumina.com). Adaptor-ligated fragments 150-250 bp and 250-350 bp in size were recovered from a 2.5% NuSieve 1:1 agarose gel (Zymoclean™ Gel DNA Recovery Kit, ZR).

The fragments were then bisulfite treated using the EZ DNA Methylation-Lightning™ Kit

(ZR). Preparative-scale PCR was performed and the resulting products were purified (DNA

Clean & Concentrator™ – ZR) for sequencing on an Illumina HiSeq.

Methyl-MiniSeq™ Sequence alignments and data analysis

Sequence reads from bisulfite-treated EpiQuest libraries were identified using standard

Illumina base-calling software and then analyzed using a Zymo Research proprietary analysis pipeline, which uses Bismark (http://www.bioinformatics.babraham.ac.uk/projects/bismark/) to perform the alignment. Index files were constructed using the bismark_genome_preparation command and the entire reference genome. The --non_directional parameter was applied while running Bismark. All other parameters were set to default. Filled-in nucleotides were trimmed off while performing methylation calling. Bisulphite pyrosequencing

Five statistically significant CpGs showing strong differential methylation were selected for the technical validation of RRBS in the PP, PN and NN samples. Bisulphite conversion was performed using the manufacturer’s protocol (EZ DNA methylation kit, Zymo Research) and pyrosequencing was performed on the Pyromark™ Q24 system (QIAGEN).

Permutation test

The statistical significance of CpG sites in the psoriasis candidate genes and eQTL loci was determined using a threshold of 33% differential methylation. The number of differentially methylated CpG sites were counted in the psoriasis candidate genes or in the eQTL loci and compared to the mean number of sites ± standard deviation in the randomly permutated samples. P < 0.05 was considered to be significant.

Supplementary figures and tables

Supplementary Figure S1. Genomic distribution of the CpG sites. (A) Illustrates the distribution of all the covered CpG sites in the pairwise PN/NN, PP/PN and PP/NN comparisons, (B-D) Illustrates the distribution of the hypermethylated (black bars)and hypomethylated (grey bars) CpG sites in the pairwise comparisons.

Supplementary Table S1. Overrepresentation of PANTHER pathways in the pairwise comparisons

Supplementary table S1. Top 2000 hypomethylated genes in PN vs NN No. of PANTHER Pathways genes Fold Enrichment Bonferroni corrected P value Cadherin signaling pathway (P00012) 29 4.70 2.85E-09 Endothelin signaling pathway (P00019) 12 3.57 3.03E-02 PDGF signaling pathway (P00047) 19 3.27 1.66E-03 Wnt signaling pathway (P00057) 38 3.13 2.48E-07

Top 2000 hypermethylated genes in PN vs NN No. of PANTHER Pathways genes Fold Enrichment Bonferroni corrected P value Alpha adrenergic receptor signaling pathway (P00002) 7 8.14 5.03E-03 Cadherin signaling pathway (P00012) 28 5.15 7.46E-10 Wnt signaling pathway (P00057) 39 3.65 1.86E-09 Gonadotropin-releasing hormone receptor pathway (P06664) 20 2.48 4.11E-02 Top 2000 hypomethylated genes in PP vs NN No. of PANTHER Pathways genes Fold Enrichment Bonferroni corrected P value Cadherin signaling pathway (P00012) 26 5.06 6.27E-09 B cell activation (P00010) 11 4.70 5.19E-03 Wnt signaling pathway (P00057) 39 3.86 3.52E-10 Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway (P00027) 14 3.50 1.13E-02 Integrin signalling pathway (P00034) 17 2.72 4.00E-02 Inflammation mediated by chemokine and cytokine signaling pathway (P00031) 21 2.47 2.92E-02

No pathways overrepresented for top 2000 hypermethylated genes in PP vs NN

Top 2000 hypomethylated genes in PP vs PN No. of PANTHER Pathways genes Fold Enrichment Bonferroni corrected P value Cadherin signaling pathway (P00012) 43 7.18 8.57E-21 Histamine H1 receptor mediated signaling pathway (P04385) 9 5.40 9.52E-03 Wnt signaling pathway (P00057) 58 4.92 2.27E-20 Oxytocin receptor mediated signaling pathway (P04391) 10 4.55 1.53E-02 5HT2 type receptor mediated signaling pathway (P04374) 10 3.94 4.80E-02 Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway (P00027) 17 3.65 1.19E-03 Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway (P00026) 18 2.90 1.28E-02 Inflammation mediated by chemokine and cytokine signaling pathway (P00031) 23 2.32 3.63E-02

Top 2000 hypermethylated genes in PP vs PN No. of PANTHER Pathways genes Fold Enrichment Bonferroni corrected P value Angiogenesis (P00005) 18 2.74 2.55E-02 Gonadotropin-releasing hormone receptor pathway (P06664) 21 2.39 4.65E-02

Supplemental data S1. PP vs PN PN vs NN and and PP vs NN overlapping genes PP vs NN overlapping genes COQ7 IFITM2 PCSK9 ZBTB47 CASC4 SLC30A2 SLC25A30 PIGL TNFRSF18 RARRES1 CIB2 HPCA GNL2 GRM4 GUK1 FGFR3 SEMA4B IFI44

IL23R TTC27 CTNNBIP1 RAPGEF2 DNM1P46 SLC6A17 MRAS B4GALNT1 TSPAN1 FBXW7 SNORD115-17 NTRK1 PROSER2 CCDC144NL MIR4252 LOC339975 WDR76 ATP1A2 DNMT3B ANKRD12 KIF1B PLA2G12A CYP1A2 RGS5 FAM57A RBM24 ZBTB48 DUX4L6 MIR147B KIAA1614 LINC00320 ITGB2-AS1 FGR TBC1D14 COX5A LOC440704 HPGDS LRP12 SCMH1 BMPR1B SCAMP5 MDM4 COL18A1 LOC283922 NBPF1 PITX2 PPCDC PADI3 SYBU PGAM5 ARHGAP29 PPP2R2C FLJ42289 ZNF683 FAAH2 CENPH VASH2 PKD2 ANPEP CD1C TNFRSF18 OTOS C1orf86 ERVMER34-1 TARSL2 TCEB3 AQP11 CNTRL C1orf86 FAM160A1 MIR5189 KHDRBS1 CAMKV FAM173B THAP3 SPOCK3 FBXL16 MANEAL PRR22 CDR2L LOC100506795 OTOP1 DEXI RAVER2 HHIP-AS1 LCT USP24 RNF223 HHIP ALDOA SLC25A44 PTK7 HHIPL2 MAPKAPK2 PPEF2 ANKRD26P1 HMCN1 MIR548F1 SSTR5 SSTR5- ROBO4 SLC3A2 GJB3 SETD7 AS1 KCNT2 CAPN14 UCP2 LRP8 GPM6A LOC100128881 GPR25 INPP5F SUOX ADAM15 IDUA HAS3 AVPR1B FAM114A1 TSPAN32 STARD13 ADCY10 MIR574 MTHFSD MFN2 ELMO3 ADPRHL1 CDK11B GABRA2 IQCK MDS2 LOC93622 EAPP ARHGEF2 DCHS2 IL4R CEP85 DISC1 GTF2B PSEN1 TSNAX-DISC1 CCDC149 MT1X TMEM61 COG6 IVD LGR6 MAB21L2 MYLK3 KIAA1324

TMC3 BBS2 TAF5L FHDC1 CMIP VTCN1 C19orf21 PHLPP2 LOC284632 SOWAHB KCNG4 SFT2D2 PHGDH HS3ST3B1 ARNT EMCN ZDHHC7 FMO1 BRSK2 ATXN7L3 FCRL3 HOPX CHP2 CRB1 MYOM1 MARCH10 TAS1R1 CCDC158 LINC00273 CAPN2 ABCA1 SOCS3 EFHD2 TSPAN5 PRSS8 LOC149134 HSPB7 TUBB4A PTP4A2 ANK2 MIR5587 SLFNL1

RSPO1 SYDE1 PIK3C2B SH3D19 B3GNT9 EPS15 POLR1D PQLC3 PLEKHG5 NAT8L CACNG3 ZCCHC11 RGS19 CHST10 MIR4695 GPR78 NTHL1 GJA5 MYL5 EPB41L5 QSOX1 GPR125 RPS15A LINC00869 LINC00623 AGPAT4-IT1 ABCB6 SUCLG1 LOC100506035 UMOD STX6 FAM63A FAM83C LGALSL C4orf22 NLRC5 GPR157 NKAIN4 DEDD2 FLJ16779 RNPEPL1 ZNF876P PLLP MASP2 MIR5684 CMSS1 FILIP1L DPP4 IDUA SLC9A5 FBXO42 TSPYL4 COPG1 SPRED2 NKX3-2 FAM195A STMN1 SLTM ZIC4 GPC1 PP14571 LCORL METRN EYA3 MIR196A1 LEPREL1 ATL2 CXCL13 PDPK1 TIE1 SCAMP4 ADAT3 RUFY3 PREPL NEUROG2 CENPT C1orf194 CEACAM21 RNF150 KYNU ACSL1 NECAB2 ZNF687 ABHD12 RANBP9 TTN ABLIM2 NTN3 CGN ETS2 MTFR2 GPR148 ARSJ CORO1A RRNAD1 TMEM242 TPST1 RSAD2 PCDH10 SLC38A8 DDOST CCBL1 LINC00208 CEP68 SMAD1 LOC400558 THEMIS2 TFAP2E LINC00092 CAPN10 ARFIP1 PIGQ ZMYM1 LEPREL2 TDRD7 FAM228A TMPRSS11F ZNF843 TAL1 USP7 NUP214 DNAJC27-AS1 DCTD AARS C1orf146 HOXB-AS3 HOXB6 DDX31 GPAT2 LRRC14B LINC00304 TMEM56 TMEM56-RWDD3 ACOT12 RNU5E-1 HOXB9 CLCN6 LOC100130691 RNU5D-1 TUBB3 MIR137HG

LINC00482 ECE1 MFF FAM13B DBNDD1 NTNG1 ARHGAP25 FAF1 ARID5A DOCK2 NOXO1 PEAR1 SLA2 PRPF38A ANO7 LOC340073 ZNF689 NR1I3 MIR3687 HS2ST1 PREB PCDHB18 FA2H CD247 LCNL1 VCAM1 LOC728537 KCTD16 ZG16B LINC00862 PSD TOP1P1 GPR155 PLEKHG4B CPNE2 SPATA17 C10orf95 KLHL20 TRAK1 ZDHHC11 DECR2 CCSAP PAH RC3H1 EIF4G1 MARVELD2 MEFV EDARADD SYNM IL2RA ITGB5 CPEB4 ESRP2 GPR89A TTC23 DRGX AHSG CLTB SLC38A8 PRDX3 APOL4 M1 TMEM44 TSPAN17 C16orf95 SLC39A12 JMJD1C-AS1 LOC285501 JMJD1C HDAC11 SLC6A7 DNASE1L2 C10orf128

AGO4 PPIF MYRIP GRM6 ZSCAN10 SRGN C1QTNF3- AMACR PTGER3 OPN4 MIR548H2 C1QTNF3 RBFOX1 LINC00840 LDHA CNNM1 ATP11B FABP6 NDE1 GPR26 PLBD1 SEC31B STIM2 AACSP1 PAPD5 ZNF438 KLK5 PDCD11 AFF1 DNAH5 C16orf70 ALOX5 CLASP2 PAK1 FGFRL1 CMYA5 ZCCHC14 C10orf54 CDH23 SNX25 SDHD UNC5C PCDHA12 RHBDL1 CYP2C19 MYOM3 MSANTD2 GAB1 GABRB2 SLC7A6 C10orf107 FAM71A GLB1L3 LOC402160 TMEM232 CLCN7 MMP21 RASSF4 TEAD4 MIR4798 PCDHA6 ABAT HABP2 PPP6R3 POU6F1 RBPJ PCDHA11 ZC3H7A SLC25A16 C14orf64 XRCC6BP1 ANKRD50 CDX1 ITFG1 PHKB ACSL5 YPEL3 FRS2 KLF3 FAM193B TOX3 DYDC2 DYDC1 C2orf71 ALDH2 HS3ST1 WDR41 SF3B3 SLK L3MBTL2 SBNO1 FRAS1 CMYA5 USP10 LOC100188947 N4BP2 RXFP2 DUSP1 MCTP1 FAM92B HHEX RPL19P12 SLITRK5 SH3TC2 SLCO6A1 SSTR5 SLC18A2 SSTR5 SSTR5- KIAA1522 PSMA3 PRR7-AS1 CSF1R AS1 KAT6B

TMEM53 GOLGA8B NREP C5orf64 IFT140 PTEN FKBP4 CDAN1 PRR7 FAM151B NAGPA-AS1 EXOSC1 SCAND2P PYGO1 GHR GRM6 SCNN1B ZNF503-AS1 MPHOSPH6 ANP32A EIF4EBP3 PIK3R1 CHP2 LZTS2 PNLDC1 KIAA1024 SIMC1 POU4F3 ZFHX3 TMEM72 TMEM72-AS1 LHX6 ZFAND6 CNOT6 CDX1 CTU2 TMEM26 UBE2D1 HAPLN3 EXOC3 GFPT2 ZNF276 TTC18 DNAJC9-AS1 DLG5 UNC45A ZNF608 MIR143HG KLHDC4 RBP3 GLB1L3 SMG1P1 PHF15 PCDHGA2 AFG3L1P ZNF518A CAMTA2 GSG1L DPYSL3 CD74 THRA RRP12 SLC39A3 ZNF629 LMAN2 ATG12 LINC00511 FLJ46300 MXD4 FBXW10 ST8SIA4 GLRA1 ELAC2 AKR1E2 BASP1 RELL1 AKAP10 KIAA0825 LOC285696 WNT9B ANK3 LGSN PTPN2 PCDHGA12 PAIP2 MIR635 TMEM180 MIR548T CNTNAP2 ROCK1 SFXN1 PCDHGA11 ANKFY1 NRP1 CYB561D1 DAPK3 TBC1D22B SYNPO PIRT C10orf53 PSD ZNF333 CCND3 SOX30 NLE1 MAT1A SLC2A13 ANKRD27 CLDN20 ITGA1 PSMD12 ITGB1 SSH1 CEACAM5 GSTA5 ARL15 SCARF1 CCDC147 ELMO3 IRGC DST OCLN GRIN2C ACY3 LGALS9 DKFZp434J0226 HIST1H2BD FEM1C C17orf99 RHOG PIGS ROCK2 ALDH8A1 MARCH3 RAC3 MS4A15 TMEM98 LOC442028 PI16 RAPGEF6 FOXK2 FOSL1 RSAD1 ICA1L PTCHD4 PCDHAC1 ZBTB4 TTC17 TMEM235 CD28 NOX3 PCDHAC2 G6PC3 MRGPRF CHST9 EPHA4 FAM184A SLC36A2 09-sep DNAJB13 KCNG2 VPS16 TNFRSF21 RAI14 FLOT2 WNT11 PARD6G DDRGK1 CNKSR3 MIER3 LASP1 CCDC88B TAF1B APMAP QKI MRPS27 ARHGAP27 JRKL-AS1 TMEM189 TMEM189- MARCH10 UBE2V1 BCAS1 PDAP1 FAM169A MIR548W TMEM80 RNU5E-1 LOC100131067 MX2 GART JHDM1D RNU5D-1 KSR1 DDX6 CBX6 GUSBP11 KCP ATG10 ANKRD13B TSPAN4 RANGAP1 SREBF2 SMARCD3 CCNH TEX2 FXYD2 FXYD6-FXYD2 PARVG KLHL18 ANLN STARD4-AS1 ADORA2B HYOU1 CCDC13-AS1 CCDC13 POC1A CDK6 PCDHA9 FAM83G AMPD3 FAM198A CADM2 ZCWPW1 PDLIM4 TMEM11 TBX10 LOC157273 FAM194A MIR4648 SOWAHA ELP5 BARX2 NPDC1 KPNA4 GATS PCDHGA7 MIR1180 LRRC10B MIR4488 CPSF3L ATP13A5 WBSCR22 CDX1 ZNF207 WDR74 MIR338 MIR657 VPS37B TRMT44 MIR4648 LTC4S MIR3065 SYT12 NFATC4 PHOX2B NAMPT GMDS FAM83G INSC YBX2 GUCY1A3 SMO TJAP1 MAPK7 B9D1 FLJ42102 ZNF701 NIPBL UBE2H ELOVL2 KCNJ18 TPBGL NCOA1 VDAC1 FAM185A ZNF318 VEZF1 POU2AF1 SOD1 CDKL3 LRRC61 LRRC1 RPL38 ATHL1 ADORA2A- AS1 KLHL3 RAC1 HIST1H3A LOC100506388 KLC2 ZFAT-AS1 VIPR1 BPHL ZFAT SLC26A8 MINK1 GRM5 NPR3 TMEM170B SBSPON GUCA1B RNF135 SCUBE2 CA9 HIST1H2AG GPAA1 PNPLA1 LRRC37B SOX6 MELK TTBK1 PNOC LOC100507194 CYB561 SLC1A2 MATN1 ATG5 LZTS1 PTCRA USP6 SLC15A3 ADARB2-AS1 MIR4520A ADARB2 PEX7 DEPTOR MLIP MIR4520B FNBP4 CCNY SF3B5 CRH SMIM13 GPS2 ST5 LOC440311 EPM2A PYCRL METTL24 MPDU1 SPI1 RNFT1 OPRM1 LYNX1 WISP3 B9D1 LGALS12 C19orf55 MAP3K4 CDCA2 KIAA0319 SMTNL2 GPR137 TFIP11 FAM120B PTK2 TULP1 SLC16A13 SLC29A2 HOXA10- HOXA9 SEC62 HOXA10 S1PR3 MIR4462 SHISA6 THY1 DOCK5 PINX1 APTX CCR6 KCNJ12 LOC283194 TP73-AS1 DPYSL2 01-dec RRP36 MPO ROBO4

PRELP NCOA2 CIZ1 MYLIP ACE PCF11 DCHS1 LY6K SOHLH1 PRPH2 FAM104A TSG101 MICALCL KIAA1432 KIAA1984 GNMT DUS1L LRRN4CL CD63 LOC100133920 PHYHD1 PPP2R5D RAB40B P2RY2 PLSCR3 C17orf61- HIGD2B BBS4 INVS TPRN ZBTB2 PLSCR3 CRTAM 09-sep C9orf84 TJP2 DUSP22 STAT5A RRAS2 TAF4B SH2D3C POMT1 TFEB LOC284080 C11orf86 CLIP3 DDI2 NOXA1 COL9A1 CD79B DRD2 GSK3A WDTC1 ECHS1 SERPINB6 LOC100507410 FLI1 CCDC93 PDE4DIP CASC2 HIST1H3H GRAPL FAR1 C2orf27A LCE3D SUFU DAAM2 CACNB1 SPI1 LOC151174 LY9 SKIDA1 ME1 LOC100130581 PLA2G16 LINC00029 POGK PFKP KIAA1244 TOM1L1 METTL7A MIR4761 IL19 LINC00202-1 KCNK5 C17orf82 MYL6B MST1R RBM34 FAS STX11 LOC100130370 PLEKHG6 ST8SIA6 CPA1 ST8SIA6-AS1 SUFU DDO ALOX12 ATF1 AGPAT6 PNPLA2 C10orf71 UHRF1BP1 ASGR2 FLJ12825 IQSEC3 LOC574538 NAP1L4 BNIP3 TSPYL4 MFSD6L TBC1D30 LECT1 ZNF408 ACBD5 ADGB DRG2 LRRK2 ZFP91-CNTF PRSS27 ZFP91 TMEM72 VOPP1 ALDH3A2 RHOF ZG16B CCDC86 EXPH5 ACTL6B HSPB9 TMEM52B SP6 XRRA1 MIR130A POP7 BZRAP1 SELPLG HOXB-AS3 SLCO1B1 NLRX1 WDR86 SOX15 TRPV4 MC2R KRT72 TPCN2 HOXA3 RASL10B ASIC1 MCEE POLR3B C11orf70 MIOS SLC4A1 BCAT1 CLCN3 GJB6 KDELC2 GUSB PPM1D COL2A1 CPA5 SOX1 CD81 ZP3 TBX4 COPZ1 CLCN4 GAS6 MOB2 CTSD NUB1 USP36 MARS UTP11L UPF3A NADSYN1 ZP3 ULK2 FZD10 CSRP1 CBLN3 PPP2R1B FASTK UNC119 FMNL3 AP3M1 ZFYVE1 C1QTNF4 HOXA5 LHX1 SOCS2 ADAMTS8 SNORD116-8 LOC100133315 WBSCR22 LOC146880 GIT2 NTF3 KLHL25 SLC22A18AS TECPR1 ST6GALNAC1 GCN1L1 LOC642846 FES EHBP1L1 ZNF394 C17orf70 TENC1 TRIM9 CD300A TMPRSS4-AS1 LOC100130705 NARF BEST3 CDK10 OVOL3 IFITM3 ABCF2 C17orf66 HMGA2 FSCN2 PLEKHA4 MRPL23-AS1 LOC100288524 NBR2 CCDC42B C19orf24 NLRC4 SYT9 FZD9 CDC27 LMO3 ANKRD62P1- PARP4P3 EPC2 MIR5692A1 IQUB CDK5RAP3 AEBP2 LOC401052 XRCC5 DCDC1 NUPR1L ITGA3 SMARCC2 NQO2 CRYBA2 ST3GAL4 CLDN3 CA10 FOXN4 COX19 WRB LTBP3 NSUN5P1 HEXDC CABP1 NOM1 KREMEN1 KCNJ5 LRWD1 DHRS7B CPNE8 PSCA TST DYNC2H1 DOCK4 LOC440461 KIF21A SLC25A25 FBLN2 HMBS TPK1 SHISA6 FAM222A-AS1 SLC27A3 LRRFIP2 GYLTL1B ABCB8 MEIS3P1 PTPN6 CHAT C3orf67 CST6 NCAPG2 HAUS1 FAM222A STAB2 LINC00636 MCAM PSMG3 C18orf25 ABCC9 MRPS31 OSBPL11 LRP4 EPHB4 GNAL DDX11 KBTBD13 C3orf22 UBE2L6 UFSP1 TGIF1 FGD4 GAA CHST2 EML3 ATG9B SMCHD1 ACVRL1 MYOM1 LRRIQ4 B3GNT1 NPC1L1 IMPACT KRT85 GALR1 CCDC50 LSP1 CUL1 ZNF521 TCP11L2 DNAJB1 LOC285419 C11orf68 ABP1 L3MBTL4 FAM109A TNNI3 RBM27 B3GNT6 SKAP2 LDLRAD4 KRT83 DNAH6 DTNBP1 MTCH2 ORAI2 AQP4-AS1 RPL6 SUMO1 SOX4 AHNAK KCNH2 LOXHD1 SNRNP35 SNX21 ARMC12 LTBP3 LOC442497 LDLRAD4 PLEKHA5 KCNJ6 BAG2 BBS1 HOXA4 TCEB3B NAV3 AMIGO3 MDN1 PXMP2 VPS41 MBD2 RILPL2 RASSF1 FRK FAM222A ICA1 PHLPP1 POLR1D FOXM1 RYBP PHACTR2 RHNO1 DGKB KDSR HMGB1 PPP1R14C SLC25A13 SSPN LEP MC5R PCDH20 LTBR DIRAS2 ZKSCAN1 SCNN1A ZNF853 KIAA1328 HSPH1

DCST2 LOC100216546 SLC41A2 IL6 MOCOS AKAP11 TMCC2 SLC4A2 SLC16A7 HOXA7 LOC284276 TUBA3C KCNC1 SMIM19 SMCO2 GBX1 LIPG DLEU2 TRIM13 CAPN1 MTBP KRT72 WIPI2 TCF3 TEX26-AS1 MEDAG N6AMT2 GLIPR2 NAB2 ADCYAP1R1 LOC644189 LINC00552 CES3 ALDH1B1 GRIP1 AMPH TINCR XPO4 ACOX1 MXRA8 KCNA6 FAM200A KLF16 FLT3 ACOT11 BTBD2 FAM151A LINC00507 CALD1 MAG TSC22D1 PRAM1 NBPF9 STX2 CCM2 IFNL4 MTIF3 ZNF816- MIR641 UAP1 KCNA5 CCDC146 ZNF321P LINC00565 ZFP28 PTPLA IRAK3 PODXL DMKN SMIM2-IT1 CCDC12 LINC00842 HCAR3 ZNF398 RINL B3GALTL LOC100129550 C10orf2 KCNH3 DPP6 DBP SERTM1 FAM81B KAZALD1 MED21 PHF14 RASIP1 HNRNPA1L2 C8orf31 CASP7 YARS2 HOTAIRM1 SIGLEC7 LINC00457 KIAA1958 DUSP16 DDIT3 NUDCD3 ZNF578 GPR68 GALE H1FNT ACSM4 GTF2I ZNF414 ACIN1 ZNF559-ZNF177 C1orf168 PRKAB1 GGACT CTTNBP2 ZNF559 SERPINA10 USP21 FGF9 C13orf35 AKR1D1 RAB8A METTL3 VSIG2 PCDH8 RAB20 GALNT11 DMWD FLVCR2 RHOV OTX2 C14orf80 ESYT2 MBOAT7 EFCAB11 WDR61 TGFB3 STXBP6 ZNF680 MKNK2 PRIMA1 THAP11 EHD4 EFS C7orf61 TIMM44 MAX CBX4 NEDD4 PYGL CUX1 SMARCA4 DNAL1 SLC25A10 CRYM-AS1 DEGS2 PNPLA8 DKFZp566F0947 LGMN GCGR EIF3C WARS BRAT1 RASGRP4 SCARNA13 KHSRP CYLD CPNE6 TFPI2 C2CD4C APOPT1 CECR1 CCL17 TTLL5 PPP1R9A KANK3 SERPINA6 ATP5J2 A4GALT WIPF2 AHNAK2 ATP5J2-PTCD1 ADAMTS10 LINC00226 CHST13 NFATC1 MAPKBP1 MUC17 PRX MYH7

FLJ36777 LPPR3 CT62 FOXP2 CDC42EP5 TMED10 ING2 CHAF1A ODF3L1 MGAM ANKRD24 BTBD7 C15orf56 KDM1B PLEKHG2 PAK6 CLCN1 ZNF700 NUBPL EEPD1 WASH2P CHP1 SDK1 PGPEP1 CRIP2 LCN8 TUBA3E BMF ANKMY2 LOC148145 GNG2 JMJD7- KTI12 PLA2G4B TXNDC12 BMPR2 PLA2G4B SEMA3C CHST8 DHRS7 SLC6A13 EFHD1 LOC283663 PILRB LOC400685 CEBPE GALNT6 EMILIN3 STRA6 LRCH4 SPHK2 REC8 WASF3 B4GALT5 NR2E3 ACHE IZUMO2 LRRC9 PMFBP1 JAM2 DUOX2 TMEM209 PNMAL2 ZNF219 OTOP2 PITPNB RHOV SLC13A4 RRAS MIR208B NPAS1 AP1B1 CD276 CDCA7L CELF5 DCAF4 CENPB RBX1 KIFC3 C8orf74 CLPP KIAA0125 SLC12A8 CAMK1 OGG1 TBC1D24 MROH6 RAB11B PPP4R4 PSAPL1 UBE2E1 LOC81691 BMP1 PLD3 ATG2B PROB1 LAMB2 PLLP SDC2 KCNN4 LINC00617 PCDHB12 TLR9 ATP2C2 PSCA HSPBP1 APBA2 CD109 ZBTB11 PSKH1 PARP10 ZNF132 GOLGA6C

ZNF107 GTPBP8 TPPP3 HSF1 SLC25A23 LINS WBSCR16 RAB6B KIAA0513 RBPMS C3 VPS18 DOK2 TRIM38 BAIAP3 LOC100506990 PNPLA6 TP53BP1 RNU6-28 FRRS1 GABRR1 PRMT7 INTS9 LRRC8E SQRDL PBLD SEC63 SYNGR3 RUNX1T1 PRKACA ISLR MOB2 IFITM10 NUP43 LOC732275 KIAA1456 TDRD12 FAM63B MYO1H MAD1L1 TMEM204 RHOBTB2 APLP1 VPS13C HNF1A ADAM22 C16orf11 FAM83A LOC100507433 CHD2 RPUSD1 REPIN1 CENPN MTMR7 PLAUR TM6SF1 TPSG1 MIR153-2 PDK2 TP53INP1 SYCE2 MAN2A2 CHST6 CDH17 ACSF2 GPIHBP1 RPL18A ISL2 EFTUD2 ZNF696 ARMC7 PDLIM2 AP1M2 ISG20 LEPROTL1 GFAP MPDZ PLEKHM1P MIR548O2 NCR1 DENND4A MFSD11 FAM74A3 NR1D1 LAPTM4B C19orf77 NOX5 MIR548H4

VSTM2B C9orf41 KRT15 EEF1D LINC00665 HERC2P10 BLVRB LOC100128593 WDR81 DLC1 EXOC3L2 TMOD3 LOC728730 PTGDS STAC2 EIF4EBP1 OPA3 PEAK1 ARMC9 MRPL20 MIR4729 ADAM2 SUV420H2 MESDC1 AVP THAP3 JMJD6 LOC100507632 GNA15 AP3B2 CCDC159 KLHDC7B RTCA IGF2BP1 WWP1 TMEM205 CERS3 COL8A1 MIR548G FMO5 EPN3 PLEC TNPO2 PLCB2 LOC100507391 SYT15 TMEM107 BRF2 GADD45GIP1 CHAC1 FAM53A IDE PIP4K2B OSGIN2 SHISA7 GNB5 LOC100133461 LINC00294 AKAP1 KIAA1875 LMNB2 FBXL22 C4orf19 PPP1R32 04-sep HTRA4 C19orf70 ANKDD1A HNRNPUL2- NUDT1 FTSJ2 BSCL2 BSCL2 SMARCD2 PENK EPHX3 BLM FAM133B FAM133DP RSF1 LRRC45 EIF3H SLC35E1 SNORD115-22 NYAP1 LOC100288346 SNORD124 SLC39A4 MAP1S ACSBG1 LOC729732 LOC100506990 SPIC BTBD17 PDLIM2 TMEM190 GABRA5 TP73-AS1 SPERT MXRA7 DPYS ZIK1 ADAM10 MIR548AN LOC283299 UBAC2 ATAD5 OXR1 SCAMP4 SNORD115 HYLS1 BMP4 FBF1 PLEC BST2 ACAN FAM211A ADIPOR2 C14orf2 C17orf76-AS1 C8orf42 FFAR1 PRSS30P C12orf23 DISP2 KRT18P55 LPL MYPOP CENPN CMC2 GALK2 BNIP2 KAT2A CHRNA2 KLK12 LITAF TPM1 SNAPC5 MAP3K14 SFRP1 ZNF331 DCUN1D3 MEF2A CRTC3 SYNRG ESRP1 CACNG6 FOXF1 HBQ1 ERCC4 TBX21 ZFAT ELANE HAGHL SLFN12L CCDC135 CHAD SOX17 UBXN6 QPRT EFCAB13 TMC6 SUMO2 ATAD2 ATG4D SYT17 ZNF575 FLJ22184 SLC52A1 OPLAH LPPR2 ATP2A1 TRIM28 ZNF490 MFAP4 UCK1 PRKD2 SRL PLCL2 PSG11 MIR4726 PBX3 SULT2B1 CETP ZNF816- ZNF321P MIR128-2 RELB FMNL1 ATP8B5P ZNF816 RRN3P2 HEMK1 C3orf18 ADCY3 SGSH MAMDC2 ONECUT3 HSF4 SHOX2 DCTN1 ALOX12 LCNL1 KIAA0355 VWA3A SLC7A14 NEB PTRF NSMF MLL4 LOC595101 TTBK1 FZD7 ENTHD2 NIPSNAP3B CD79A BANP PCOLCE GPR55 SERPINB2 ZCCHC7 TMEM145 LOC100287036 ANKRD11 NAPA-AS1 WDR38 TM9SF4 NAPA COL15A1 GIPR SNORA64 SNORA10 ZNF462 LCN9 CNBD2 NUMBL MIR548Q AP2S1 PRSS41 FGFR2 PIWIL3 MYBPC2 PPP6C PRPF31 ZNF19 SMAGP APOBEC3C SEC1P UAP1L1 PCSK4 SLC6A2 MIR5692B FEZF2 CEBPA-AS1 GPR107 MBD3 CDH16 CHRNB4 UBA3 ADCK4 AMBP GNA15 RHOT2 RGS11 ACPL2 PRG1 TSC1 PLIN5 ACSM5 HS3ST6 LRCH3 KCTD15 DMRT1 ANGPTL4 SCNN1G FAM211A DCK LOC400685 DNAJB5 BEST2 DOC2A INO80E DHRS13 WWC2-AS2 ZNF57 CCDC180 NFIX MT1DP ETV4 DNAH5 TRPM4 FAM129B ZNF728 ATP6V0D1 KCNH6 DAB2 RPS19 FNBP1 PPP1R13L SPG7 CCDC68 DDX46 NLRP2 C9orf169 FAM83E PRDM7 FBXO17 SLC35A4 BSG TUSC1 PTOV1 FAM86A HIST1H2AM RPS5 HIST1H2BO RNF126 NPDC1 NLRP12 C16orf96 DOCK10 MAN1A1 TJP3 CORO2A TICAM1 KIAA0430 LOC100996307 MX1 CHST12 APOC1 UGCG LIPE NDUFAB1 MCAT SUN3 DHDH ORM2 CCDC8 CYBA LOC100133461 ANKIB1 RASGRP4 UBAP1 SAE1 BEAN1 CXCL1 ACN9 NLRP7 MIR3134 KCNA7 LOC100130894 VAC14 PCDHA4 PLOD3 PRTN3 RABEPK RCN3 C16orf90 IMPDH1 NKX3-1 C19orf77 GAPVD1 FPR3 RANBP10 LOC407835 NEFM CDC25B LHX3 GPX4 CFDP1 CDK20 LOC642236 CSRP2BP FAM219A ARHGAP33 MBTPS1 BICD1 SURF1 BCL2L1 TRPM3 FKRP MLST8 NAP1L1 LIN28A ZGPAT HABP4 SEC1P NTN5 USP31 PRTG MTF1 WFDC5 RAPGEF1 FCGRT ZNF785 RTEL1- TNFRSF6B GNG13 CNIH4 RTEL1 MAMDC4 NAPSA COX6A2 OSGIN1 AKR1C2 JPH2 SLC28A3 PRKCG TPSG1 SNHG16 ARHGAP21 SS18L1 RGS3 EPS8L1 AMFR C19orf45 SPOCK2 UCKL1 GOLGA1 CDC34 DYNC1LI2 WFDC2 SCYL1 PKIG SH2D3C ACSBG2 CIRH1A PRODH BSX RSPO4 CRAT GPI FOXC2 MYL3 FEZ1 GNAS SURF1 SURF2 ZFP36 ABHD15 LOC100302640 LPCAT3 FERMT1 ADAMTS13 CYP2A6 RAP1GAP2 LOC100129931 NUAK1 EPB41L1 GALNT12 TTYH1 ALDH3A1 DPPA5 PUS1 EEF1A2 KLF4 LILRA1 PDE6G MTUS2-AS1 KIF25 MTUS2 NKX2-2 SVEP1 DNAAF3 ATP6V0A1 BBS9 CLDN10 CCM2L C9orf106 ZSCAN18 FAM171A2 CPNE3 CLDN10 RALY RNF208 HAUS8 BZRAP1-AS1 BZRAP1 DCAF13 AVEN PPP1R16B DOCK8 FBXO17 SMG6 CCDC180 LOC100499484- TMEM54 TRADD ZNF831 C9ORF174 UBE2M GPR179 TMEM48 CNTNAP4 SSTR4 C9orf62 C20orf96 FZD2 LOC100527964 LHX4 IRF8 CYP24A1 FOXB2 BPIFA4P UNC13D TSPAN15 SNAI3-AS1 COL18A1-AS1 TMOD1 UQCC ARRB2 WEE1 TNFRSF13B BACE2 LINC00094 GPCPD1 TBX4 C11orf58 LOC100653515 CSTB SLC35D2 RBL1 SLC9A3R1 LOC100499227 KCTD1 MAPK1 PTGES2 PMEPA1 TMEM235 CPM SAMD1 TEF SIT1 MYLK2 VMO1 MIR499A PKM DRC1 PISD GNA14 MIR499B CACNA1G-AS1 AGPHD1 FSHR CYB5R3 KIAA0368 LOC100505783 SLC16A3 ZNF555 LBX2 NF2 TPRN SLC13A3 PYY NAGS CECR5-AS1 ZNF283 AOX2P CECR5 PCGF5 PDRG1 HLF HIF3A MARCH4 RFPL2 KIAA1217 WFDC3 SREBF1 LOC100130264 ZSCAN18 PRSS56 CHADL LOC100130539 SLC24A3 LINC00469 LOC100131691 MZF1 CPXM1 PARVB KCNIP2 BPIFA3 CCDC42 PKP4 GGT7 SUN2 AGAP11 MMP24 MGAT5B MIR3648 MIR3687 HIC2 USP18 C10orf90 LZTS3 PHF12 C21orf59 GGT5 DGCR6 EBLN1 SLC9A8 LEPREL4 FKBP10 C21orf2 DNAH12 NOL12 PDCD11 TCEA2 MPP3 PRR5- KRTAP10-2 SYNPR ARHGAP8 PRR26 COL20A1 CD300LG RNF212 SMIM20 TMEM255A PNLIPRP2 PRPF6 COIL KIT SULT1B1 BCAP31 ZNF365 RBPJL SLC2A4 AGXT2L1 FIG4 KAL1 PPAPDC1A MAPRE1 NFE2L1 CETN3 NUP205 FGD1 DOCK1 NNAT TEX14 CCNJL SHC3 WWC3 DUSP13 NNAT MYO15B HOXA10 ST6GALNAC6 ITIH6 METTL10 CASS4 CANT1 GPR158-AS1 DNLZ KIF17 AK4 GPR158 CEP250 KRTAP2-1 GPM6B ECE1 CNTN2 KIAA1462 NKAIN4 UNK FBXO44 HCRTR1 PLA2G2C FAM13C VSTM2L C17orf104 RNF186 TNFAIP8L2 FCN3 MMRN2 SPATA2 LOC440461 TMEM56- RWDD3 NVL PPT1 FOXI2 COL9A3 SRP68 SLC22A15 TTC40 ARPC5 PRKCQ BPIFB2 SENP3-EIF4A1 SENP3 CR1L DTX4 ALPL CCDC3 C20orf166-AS1 FAM20A PRKAR1A DNHD1 SPSB2 SPATA6 C10orf76 FAM110A PITPNA CADM1 ARHGEF25 FCRL6 PITX3 TGM3 WFIKKN2 CHD4 SLC5A8 TAS1R1 NOL9 PROSER2 C20orf196 LINC00469 LOC400620 SPESP1 ASCL4 CAPN2 NSUN6 SNAP25 HN1 TEKT5 FICD USP48 KIAA1598 PLK1S1 CCDC144A NLGN2 ZMYM2 GUCA2A FAM178A CBFA2T2 PIPOX STX16 STX16- LRRC3C SYNDIG1L FAM69A LDB1 NPEPL1 TBC1D3P1-DHX40P1 HKR1 ZDHHC22 PDIA3P FRMPD2 NELFCD AANAT SIGLEC14 LOC283683 ZBTB7B BTRC LOC149950 EIF4A3 ZNF331 WFIKKN1 ADAM15 VENTX DLGAP4 BAIAP2 BAIAP2-AS1 KIDINS220 CHTF8 PIGR PIP4K2A SOGA1 SNORD42B MRPL33 EFCAB5 SLC2A5 NODAL DZANK1 NUFIP2 CNTNAP5 C1QTNF1 C1orf127 TDRD1 PROCR DBF4B FAM83D URI1 ZMYM4 USP6NL ZFP64 MIR4316 LOC388813 C2orf53 CYP4B1 MKX DOK5 MIR3186 DGCR8 EHD3 AKNAD1 CDHR1 GATA5 ZNF232 COPS4 VPS54 SEMA6C ACTA2 C20orf26 RPL29P2 MRPS27 PLAGL2 PTCD2 PPP3R1 LEFTY2 PRLHR POFUT1 NT5M FAM24B- CUZD1 LOC399815 RRAGD RBM38 GPR137B FAM24B SLC32A1 RPL27 IL7 C2CD2 UBAP2L PDE6C TNNC2 MAP3K14 CCDC166 BCL2L13 IGSF9 BTBD16 TCFL5 ZNF236 C9orf129 TGM4 TRIM58 UTF1 BHLHE23 RNF165 WIF1 GPR27 SCNN1D HNRNPF IFT52 CDH7 FAM213B RBM38 NALCN SENP5 MMEL1 FBXL15 MIR5095 ABHD3 ASPG FGA TNFRSF25 RBM20 GATA5 CLUL1 NIPA2 SRD5A1 SLC25A34 CSTF2T TPD52L2 CCDC102B LINC00593 LOC642366 PHC2 HERC4 SMOX SNRPD1 C15orf59 FLJ46906 LDLRAD1 C10orf105 E2F1 CDH2 LYSMD4 LOC100132352 ACOT7 XPNPEP1 MATN4 COLEC12 PGP TUBBP5 FMO5 SPOCK2 TFF1 TMEM241 PRSS36 NKAIN1 ADIPOR1 KCNMA1 TMEM50B RBBP8 KXD1 SPOCD1 FLAD1 MMS19 RRP1B HSF2BP DSC3 RNF149 MTMR9LP LOC100131234 C10orf95 PCP4 NETO1 ARPP21 CELSR2 MFSD4 SORCS3 LOC100133286 SALL3 ENTPD3 OLFML3 PUSL1 SORCS1 KCNE1 EIF3G LRRC3-AS1 GPR62 GON4L C1orf86 EIF3A LRRC3 F2RL3 DPPA2 KDM5B MUL1 PTF1A CHODL TFPT PRPF31 OBSCN HDAC3 C1orf145 PODN CTBP2 USP25 P2RY11 DUSP5P1 MAT2B RHOU BCL9 MUC5B CLIC6 EVI5L LINC00473 ANAPC16 CREB3L4 DKK3 GRIK1 TNNT1 T FAM35A LAMC2 CABP2 LOC339622 RPS15 NAPEPLD ARCN1 LAD1 RAB30 OLIG2 ISYNA1 SVEP1 ADAMTS20 TAS1R3 MOB2 DUSP8 SLC5A3 STRN4 CCDC30 SLC24A6 ICMT TH KCNJ15 PRSS57 TFB2M GPC5 RCC2 MRGPRG-AS1 ABCC13 MIR4745 NKX6-2 FGF14 CELA3A MRGPRE CARD10 ZNF781 LOC100128239 PPP1R14D WASF2 CHRM1 CYB5R3 CLEC11A CCND2 GABPB1 FOXJ3 CABP2 RNF185 SIGLEC17P ORAI1 RAB11A EPHX4 UNC93B1 RIBC2 SULT2B1 LOC100128770 MT1DP COL11A1 ST5 SGSM3 FXYD5 ZFP1 CCDC47 MROH9 SCGB1A1 ASCC2 MVB12A SCN4A HID1 C1orf233 C11orf30 TXN2 SNORD32A MRPL35 MEIS1-AS3 KAZN PIWIL4 UBE2L3 KLK6 SCN2A INHBB C1orf94 RIN1 CABP7 RETN OGG1 NABP1 SF3A3 DDB1 SSTR3 RSPH6A MIR4763 AGPAT9 SP140 RHBDL2 ARAP1 MIRLET7B FBXW9 SLC1A3 GGTLC1 HPCAL4 CYP2R1 KLHL22 SLC1A5 PCDHA4 MROH8 LINC00466 MIR1237 LRP5L CD320 HIST1H2AL KCNS1 CACNA1S CHKA PVALB KANK3 SMC5 MORC3 MIA3 FAT3 IL17REL HAPLN4 CNIH3 ZNF74 UBE2J2 SNX19 MCM5 FUT6 ABCC8 FBXW4P1 MMP23B OPCML APOBEC3H RTBDN PTPMT1 OVOL1 SEC14L3 ARHGEF19 KBTBD4 MAPK11 GCDH PHOX2A PKDREJ TMEM54 TAF6L ST13 CLEC17A NBEA MIR548F5 DNASE1L3 B4GALT2 RAB1B CECR1 FOSB DLEU7 SDHA ACOT11 PKP3 LOC100128531 KLK10 CHEK2P2 TRIP13 MRPL20 FAM168A SLC35E4 LAIR2 LOC283692 CCNI2 RFWD2 ENDOD1 ZC3H7B PLIN3 CTNND1 TMX2- PARN PCDHB16 ADCK3 CTNND1 BID RAB3D FOXL1 PCDHGA9 ARF1 AAMDC ZNF70 ZNF442 ADCYAP1 ARSI TP73 RNU6-83 LOC150381 USHBP1 LOC284260 DUSP22 SERINC2 TP53AIP1 AIFM3 LRP3 ST8SIA3 RPL10A PVRL4 DRD4 ZBED4 S1PR2 MBOAT7 GUCA1A NEK7 RAB6A APOL5 CEACAM3 ZNF606 LOC100128398 LOC100287632 ZNF672 QSER1 SLC25A17 LOC100505622 LOC440900 LOC100289495 PARK7 PSMC3 XPNPEP3 IL4I1 NUP62 PECR CCDC129 UBR4 NDUFS8 DEPDC5 ZNF444 CDKN2A PABPC1L CDKN2B-AS1 OPRD1 KCNJ1 TPTEP1 EPOR MAATS1 TGFBR1 LRRC8D B3GAT1 IGLL1 AKAP8L ZNF141 SUSD1 AMPD2 ATHL1 SLC2A11 LSM14A UPB1 SMPDL3A TTC16 AIM2 ART5 ADORA2A-AS1 FAM83E POM121 GSTM3 RGL1 ARNTL RASL10A TULP2 C9orf170 LOC440600 CNST PTPN5 PICK1 ZIM2 PEG3 HIST2H2BA CCDC172 PLEKHN1 CEND1 LOC730668 DIRAS1 TOLLIP WDR64 RFX4 NPPB LOC255512 GP1BB DOHH SLC18A3 TM9SF2 FLJ37453 MRGPRE RAB36 ZFP14 FGF4 TTC9 CNR2 ALDH3B1 HPS4 ZNF665 STUB1 ZSCAN10 NKAIN1 RELT GTPBP1 SLC25A23 CNTROB VMAC GNG12 EED CBX7 ANGPTL6 CHKB-CPT1B HOXB4 ISYNA1 KCNA3 CBL CPT1B TRMT1 MOCOS ARMC6 RCSD1 PAMR1 PNPLA5 CC2D1A MPND RINL RASAL2 MTA2 PDZD4 ZNF829 CYP20A1 TTC7A KLHDC8A P2RY6 LOC100873065 PEX11G MIR663B NCOA5 ANKRD30BL VWA1 AP2A2 KIF4A DKFZp566F0947 MIR3648 MIR3687 LYPD6 HPDL MPPED2 CTPS2 HAS1 RNF123 STAT1 NSUN4 PRR5L LOC92249 RAX2 PCYT1A PLEKHM3 C1orf105 SLC22A11 HAUS7 PRAM1 GALNTL6 CYP27A1 SHCBP1L RBM4 PCDH19 C19orf66 MRPL36 NDUFS6 TFF2 C1orf106 AMOTL1 LOC286467 ZNF563 FHL5 IL17RA RBP7 SLC22A12 BCYRN1 ZNF709 REPS1 TTC28-AS1 FBXO2 LRFN4 PLXNB3 HSH2D PDE4DIP CCDC13 EMC1 PC IL1RAPL1 FKBP8 FAM204A C4orf22 SESN2 DIXDC1 PCDH11X GRAMD1A NDRG2 TBC1D9 ZNF684 NUP98 PPP1R3F SPRED3 PGPEP1L ANKDD1B ERMAP NLRP10 PNMA3 CPT1C GAS8 FBLL1 SYT6 LTBP3 IRS4 SBNO2 MYO1C DUSP22 IGSF3 NPAS4 PPAP2B PTPRS PGR ANKRD30B GPR146 ADAMTSL4 LOC101054525 LPAR3 STXBP2 GIPC3 TSPAN33 PKLR IRF7 RGS16 ZNF559-ZNF177 ZNF177 ZNF726 FNTA CCDC19 BDNF ATP1B1 MRPL4 ZNF30 FLJ46284 RYR2 SLC39A13 LAPTM5 SPC24 ELMOD3 FAM102A PIK3CD VPS51 PSMA5 ZNF526 ERCC3 COPB1 EXOSC10 CCDC83 LOC148709 HIF3A CCDC140 PAX3 CTSF NUDC DDX6 TNFRSF25 UQCR11 SPHKAP SERPINH1 POU3F1 BDNF LUZP1 C2orf40 PKNOX1 CSRP2 LEPRE1 DCDC5 NUAK2 ANKRD39 CECR7 NTN4 TTC22 FCHSD2 ENO1 HOXD4 MIR10B SCARF2 FZD10 NBPF7 NPAT ZBTB37 PRORSD1P IRX2 ANHX LMX1A NTM C1orf200 TSN SNX18 KL MPZL1 KDM5A BEND7 DARS PCDHB1 ARHGAP28 LMOD1 PPFIBP1 LRRC20 WIPF1 EEPD1 MIR4748 SRGAP2 FBXW8 LOC100130992 SGPP2 SLC26A5 CHERP PARP1 PRIM1 TACC2 UGT1A KCNT1 MATN3 TNFRSF4 LIMA1 VAX1 C2orf78 TRNAU1AP ZAP70 PER3 POLE NUDT5 MEMO1 KCNK1 ZNF343 MAD2L2 CDK17 TMEM135 PROKR1 SYS1 SYS1- FFAR4 DBNDD2 VWA5B1 RPH3A TBC1D10C CYBRD1 UTF1 CECR3 MPL ANKRD13A CTSC GALM LOC283692 CPEB1 ALG12 PTCH2 ANHX ADRBK1 RNASEH1 ONECUT2 LOC440970 ALX3 WNT5B KCNJ11 WDR54 NTSR2 GHSR RNF115 FOXN4 IL10RA BUB1 EN1 ARHGAP24 PKP1 SCAF11 LOC100240735 STK39 MAP3K19 ZNF827 DISP1 RNFT2 TBX3 HSPE1-MOB4 MOB4 SLCO6A1 IPO11 C1orf35 KRT81 PCBP2 TXNDC9 KLC4 DOK3 NOL9 LOC643770 OAS1 WIPF1 MESTIT1 FAM135A MEST LOC388692 MTERFD3 HOTAIR MSH2 MUC12 PALM2-AKAP2 VPS45 TRAFD1 HOXC5 HOXC4 FLJ30838 CACNA1C CCDC136 PPP1R26 RHBG CACNA1C-AS1 ARL6IP4 LINC00152 ZNF398 FBXW5 C8G DCAF8 TMEM19 SCNN1A PAX8 PAEP PAK3 HSPA7 PHB2 LINC00460 RALB C9orf169 NBPF10 ABCB10 EMP1 SACS VWC2L-IT1 VWC2L WLS GNG12- AS1 SH2D2A KRTCAP3 MYF6 ITM2B LOC100506474 ARL3 SFXN2 LINC00856 UXS1 LMBR1L LINC00558 LRPPRC CTSD ARL3 MIR26B NCKAP5L TNFAIP2 TISP43 LOC646743 TMEM233 HIPK3 HDLBP CD63 LRRC16B WDSUB1 GSX1 SLC35E3 KANSL3 CCDC63 SLC7A8 TANK CCNK B3GNT4 NR4A2 MPHOSPH9 NFATC4 CFLAR CFLAR-AS1 MIR149 TRAF4 SLC38A6 PP14571 CD163L1 TBPL2 ATG9A PDE4A AEN WDR33 DDX23 TBPL2 GLI2 QTRT1 FURIN FAM126B AQP2 TMEM229B CCDC74B-AS1 FFAR2 ZNF597 NAA60 BOK-AS1 LHX5 C15orf62 CREB1 RTN4 LOC728392 GLB1L HSPB8 GANC AMMECR1L MLPH TMEM88 ECEL1P2 LPAR5 C15orf53 COBLL1 POU4F2 FKBP10 USP39 C2orf68 EMP1 SIN3A MIR2467 NPEPL1 KRBA1 STX16-NPEPL1 CXCR2 EIF4B SNORD115-13 PPP1R7 RPS4Y1 KRTAP10-6 RNF144A CTDSP2 RMDN3 C2orf50 FLJ33534 LOC100128531 MIR3675 KIAA1671 SNX17 CLEC9A SLX4 DGUOK KIF17 EMID1 ECEL1P2 BCAT1 C16orf45 CAB39 FOXE3 SCN10A HPCAL1 LOC100335030 MPV17L NEU4 TAGLN2 ZXDC CERKL CKAP4 SSTR5 FNDC4 RCOR3 FAM153A DHX57 WSCD2 PRMT7 TRMT61B RNU5F-1 FLJ41649 NEURL3 A2ML1 SCNN1B PCYOX1 PLD5 GPR111 LOC375295 KRT8 RNF157-AS1 ALMS1 SLC18A3 POU3F2 UCN SP1 TRPV1 RGPD1 PAX6 ABCA13 FBXO41 CDK2 PMEL PLCD3 IL1R2 LHX5 TRIM24 ZEB2 BEST3 GP1BA GPR1 LECT1 C1orf172 TBR1 SDS DLX4 TAF1B FOXG1 MRPL37 CUL3 TRIAP1 GATC LOC284009 PPP1R21 ARNT2 TDRD5 C2orf54 CLIP1 B4GALNT2 AFF3 NR2F2 MIR1469 MICU1 ITGB1BP1 PRMT8 RAP1GAP2 STAT4 CLDN9 SLC22A18 CRIM1 NFE2 C18orf56 HSPE1-MOB4 ATXN2L TMEM179B RAB1A C12orf56 PSMA8 SNRNP200 PARD6A ACD DBX2 MAL DYRK2 ADNP2 RGPD3 SERPINF1 CCDC92 STARD7 TBC1D15 PRSS57 THSD7B HOXB6 ISM2 HIBCH ERC1 TMEM190 LINC00471 WIPI1 SPATA2L DNAJB2 LRTM2 ZFR2 FMNL2 NR2F6 DHRS11 SOS1 LOC101055625 S1PR5 KCNH7 HOXB2 HOXB- IGLON5 AS1 AAK1 PRPH KLK6 PTPRN EPN1 NXPH3 SMPD4 TFCP2 FUT6 CAMKMT KLF11 NFATC1 PRKAG3 SLC4A8 ZSCAN5B MRPS5 ASB3 GPR75- SPDYA MIR1227 ASB3 PHLDA1 WDR88 CCDC108 CNRIP1 LYL1 CXXC11 FAM222A-AS1 LOC100505495 ZBP1 MIR3196 CCDC97 GPR113 C12orf4 ZNF812 RBPJL STON1- GTF2A1L SHISA8 TGFBRAP1 STON1 METTL20 OTX1 DBNDD2 BIK PLEKHA3 CCDC85A C12orf29 EPCAM PHACTR3 TAGLN3 TFPI RTKN TBX5 ABCB11 TLDC2 ABCC5-AS1 PTH2R LIMS1 MORN3 ESPNL DIDO1 SH3RF3 C4orf48 CPS1 SCTR C12orf65 SH3RF3-AS1 ZNF217 TRMT10A RUFY4 R3HDM1 PRH1-PRR4 SIX2 SPO11 NBLA00301 HAND2 OXTR ABCB6 CASC1 SIX2 SNAP25-AS1 RICTOR PEX5L HADHB DENND5B CDC42EP3 RBPJL C5orf15 MSX2 AGBL5 PPHLN1 M1AP DBNDD2 LRRC4 GLP1R CAPG KCNC2 CASP10 FAM182B PRRT4 FABP5 FARSB CRADD LOC541471 KCNB1 ELAVL2 ARSD COL4A4 KCTD10 STMN3 ACSS1 IDH3G CD160 SRBD1 TMEM233 SNAI1 PTGIS TMEM9 FAM89A PCDP1 LTBR SAMD10 HELZ2 DUSP5P1 MIR663B RHOU PIDD ANKRD30BL IKBIP ZBP1 LINC00176 CCDC169- SOHLH2 CCDC7 TMPO HOXD9 SOHLH2 C20orf197 MIR1-1 SFXN4 DZIP1 USP37 MIPEPP3 TGIF2 NDRG3 MOB2 CHAMP1 ASXL2 LMO7 DNAJC5 KCNB1 ATM RHBDL3 CAPN13 SLITRK1 CST7 GTPBP5 SLC12A6 FLJ25758 HAAO TNFRSF19 LOC284798 UCKL1 RASL12 FXYD1 KCNK12 CDX2 LOC100506385 PCIF1 SSTR5 SSTR5- SUGT1P3 ITGB2 ITGB2- AS1 PLA2G4C MYO1B TPTE2P5 AS1 SDCBP2-AS1 FKBP1A-SDCBP2 ENPP7 BTD FAM117B EBPL POFUT2 ASIP ZNF461 NR1I2 COL4A3 PAN3-AS1 CDC42EP1 MYL9 CCDC74A LOC100506229 NDUFA10 DLEU7 CYTH4 SLC13A3 AMOTL2 PRSS35 RHOB DACH1 APOBEC3D MACROD2-AS1 MACROD2 SIAH2 MIR4478 FHL2 IFT88 ZNRF3-AS1 LINC00261 RNU6-81 RNF4 MARC1 LOC150776 KIAA1704 EFCAB6 SNAI1 FOXD1 KRTAP5-5 PLCL1 TFDP1 CCRL2 MIR155HG PCDHB3 TRIM5 MOGAT1 RNASEH2B KCNMB2 CHODL TFAP2A AP5B1 IQCA1 ITGBL1 GRK7 KRTAP21-1 DPYSL2 LPAR5 SPDYA CUL4A CMTM7 KCNE1 ADCK5 LAG3 HNRPLL RCBTB1 TGFBR2 AGPAT3 DMRT3 KRT6A FAM168B TPTE2P6 CNTN6 C21orf58 DNAI1 SELPLG ACVR1C LINC00598 ITIH4 APP NFIL3 HVCN1 METAP1D PDS5B ZBBX ITGB2 ITGB2-AS1 SRSF4 COX16 TMEFF2 ADPRHL1 TNRC18P1 CECR5 SPAG6 VASH1 ARPC2 ATP7B HRH2 NCF4 H2AFY2 HSPB6 CNPPD1 SUCLA2 EGFLAM PKDREJ AVPR1A SPO11 SPATA3 F10 ZNF366 LOC90834 FLJ31485 TTC28 AQP12B SLC25A15 RGS7BP UPB1 ADORA2A-AS1 PCDHGB3 PCDHGB2 PCDHGA8 PCDHGA9 PCDHGC4 PCDHGB6 PCDHGB5 PCDHGB4 PCDHGA2 PCDHGA3 PCDHGA1 PCDHGA6 PCDHGA7 PCDHGA4 PCDHGA5 PCDHGA10 PCDHGA11 PCDHGA12 PCDHGC3 PCDHGB7 PCDHGB1 RTN1 COLQ EML4 MEDAG PCDHGC5 CELSR1 NAT9 HYAL2 SEMA4F GJB2 FGF1 CRKL CPB2 CPB2- PLK5 FAM153B LRRTM1 AS1 PP7080 FLJ46257 PCDHGB3 PCDHGB2 PCDHGA8 PCDHGC3 TMEM86B SYNJ2 ARHGEF4 SLC15A1 PCDHGB7 A4GALT PCDHGB6 PCDHGB5 PCDHGB4 PCDHGA2 PCDHGA3 PCDHGA1 PCDHGA6 PCDHGA7 PCDHGA4 PCDHGA5 PCDHGA10 PCDHGA11 PCDHGA12 PCDHGA9 PCDHGC4 PCDHGB1 PCDHGC5 LINC00486 ENG NHEJ1 NALCN IRX4 NCAPH2 HOXD12 FBXW5 GBX2 RALGAPA1 SGCD LINC00634 ADRA1D HENMT1 EHD3 C14orf132 TRAF3IP2 NHP2L1 C22orf46 ZIC4 CAPN9 TGFA TCL1A MCUR1 EWSR1 CTNNAL1 PTGES3 FER1L5 MPP5 SCML4 MGAT3 C2CD2L TEX22 LOC100505695 C14orf180 FUCA2 ZNRF3-AS1 SPTLC2 CRIP2 C2orf83 SLC25A29 MGC39372 YDJC CAMK2A CRK CHRND RCOR1 HIST1H4J AP1B1P1 PRRT4 TMEM221 ATXN7 KLHL33 LOC100652739 NCAPH2 SCO2 RGS3 PSG11 CD96 LINC00521 CREB3L2 C22orf23 TTF1 CMPK2 DCP1A STON2 STEAP1B TAB1 RPS6KA1 HHATL FSTL1 TCL1B SSPO GSC2 ZNF697 SPRY4 IP6K2 SYT16 LOC442497 HSCB IFI16 UBR2 NUP210 CEP128 GIMAP8 NIPSNAP1 HOXA11-AS LRRN2 GFRAL IL17RE MIS18BP1 HOXA11 LIMK2 DNAJB12 RASA4CP MAPKAPK3 NOVA1 EPDR1 TSSK2 SLC16A12 MIXL1 CCBP2 BAZ1A RFC2 RAC2 ASCL2 CDHR5 NEK4 ALDH6A1 LOC100506585 TUBA8 FKBP2 TTC12 SLC2A2 IRF2BPL ADCYAP1R1 GRAP2 SIPA1 JAM3 GOLGA4 SIX6 ABCB1 MEI1 JAM3 LRMP OSBPL10 SLC7A8 FLJ43663 RABL2B HOXC4 RASD1 SIDT1 ABHD12B NFE2L3 ADORA2A-AS1 NXPH4 CCDC144NL H1FOO GSTZ1 ZKSCAN1 RRP7A CLPX ARL5C RYK PAPOLA HR ZNF860 CD300LF SPATA20 LEKR1 SLC7A8 NSMCE2 TCTEX1D2 UNQ6975 MIR4785 GRIP2 PRKD1 TG SLA RHOA IL12A UBASH3A KLHL24 KIAA0391 SPAG1 DRD3 SLC26A1 HHATL MAP3K13 ASB2 PPP1R42 SLC35G2 KCNQ5 PRSS45 IL1RAP TMEM179 ANXA13 BHLHE40 BVES ZMYND10 RAF1 PLEKHH1 GNAQ LMCD1-AS1 TNFSF8 GRIA1 UQCRC1 ELMSAN1 PTGS1 CCR5 DKFZP434A062 TNFRSF1B LACE1 PRKCD CDH24 GPSM1 FLJ25363 ISPD CASQ2 LOC100506025 EIF4E3 GPR27 PRKCH GK SPSB4 CDH23 C10orf105 PGAM2 ATP2C1 C14orf159 FHL1 FETUB LAG3 AEBP1 TRIM59 HHIPL1 RCC1 RAB5A HOTAIR CLU BHLHE40-AS1 DHRS4L1 ZC3H12A DLG1 PRICKLE2- LOC400043 MUCL1 AS1 SIX1 HSPA6 SPATA16 DNMT3A MAFG LOC730091 EXD2 DARC STAB1 LOC728012 LINC00470 LRRC31 FBLN5 PDPN SHQ1 TMEM110 TMEM110- CHI3L1 VSIG10L MUSTN1 SFTA3 MKNK1 LSAMP C1QL3 POMC ZBTB11 PLEKHD1 CYMP PRR23A LOC442028 LOC729683 TEKT4 COL6A6 XRCC3 YARS CRELD1 CD79B MIR3127 USP13 MIR548AI TRAF3IP3 ZNF620 MIR647 MIR1914 CBWD2 KAT2B ARHGAP5 WNT2B SEMA3G SLC36A3 BBS7 WNT5A SPTSSA ARHGEF16 C3orf55 CNN3 RSPH9 PLAG1 KIF9-AS1 ESR2 LOC729970 KIF9 COG5 OR13J1 MIR1224 AHNAK2 LMOD1 ROBO2 TMEM65 TTLL10 PPARG FOXA1 ELTD1 ILDR1 NBPF3 SDE2 CAND2 FBXO34 ADAM30 SCAP FLJ39051 CERS2 ST3GAL4 TPRA1 TMEM30B INPP5B ARIH2 PTPMT1 ITGA5 RBP1 MYO5C DHCR24 CEP70 LOC100132078 VRTN ACTL6A RHCG LINC00568 SCN11A GATM GATM- IL10RA NPHS1 MAP6D1 AS1 GPR161 HHLA2 MOB3A LINC00578 RARB C15orf56 PAK6 TNN EIF1B-AS1 OSBPL10 ZNF208 PCDHGA6 ZNF860 LOC283761 TNFRSF1B RTP2 MIR1914 NHS PTPN23 DLL4 LEPR PIGZ LINC00114 BARHL2 ABHD14B C15orf52 NUP210L ZNF589 ABHD14A- ACY1 ABHD14A SERPINA12 NEK4 STRA6 C1orf204 MIR548A2 ADAMTS9-AS2 WDR82 S1PR4 ANKRD18DP CA12 PRDX1 SLC25A26 CCDC96 LOC285000 PRRT3-AS1 LOXL1 IL12RB2 PDIA5 LOXL1 RGAG4 AGBL3 TAGLN3 LOXL1-AS1 SLC9C2 EGFEM1P MDK INSRR NTRK1 NMD3 MEX3B ARL8A VWA5B2 CLCF1 LOC100130987 C17orf62 THRB TCF12 KCNK2 KIAA0226 ZNF385A RBBP8NL SLMAP MAP2K5 KMO MON1A PROCA1 LOC100009676 FOXP1 RBPMS2 CDC42 MORC1 IL17RA LOC100128750 PRRT3 NEO1 EIF2B3 LMLN PRR23A STAU2-AS1 CCDC51 BNC1 TRIM45 SUCLG2 FLJ34208 ACTL7A PFKFB4 IQGAP1 LCE3A SLITRK3 S100P DIAPH2 BSN LRRC28 FAM189B GPR160 CCDC152 LOC100288637 EIF4E3 GABRG3 SFPQ CLDN11 MAK IZUMO1 SLC41A3 HERC2 FAM78B ARPC4-TTLL3 ARPC4 MRVI1-AS1 LYVE1 CHRND CLSTN2 CATSPER2 GPA33 CAND2 LINC00277 CIZ1 LINC00189 ABCC5 MIR548H4 LOC100506023 MAP4 KAZN SLC6A1 TMEM51-AS1 TSPAN33 SLC6A1-AS1 ISL2 CEP350 RBM15B FOXD4L1 MYO5C ENTPD3-AS1 C15orf40 PLA2G5 RAD54L2 TMEM37 MGAT3 FAM86DP SPINT1 CD58 PDZRN3 IGFBP5 TBX5-AS1 NDUFAF3 ANXA2 LOC401980 PPP2R3A LOC90834 IQCA1 FEZF2 NEIL1 SYNC CMTM7 MUC20 EREG GATA2 RASGRP1 DNTTIP2 TOPAZ1 MDFI CCDC152 WWTR1 DUOX1 ZNF648 CSPG5 CBX5 SLC16A2 GP5 SNX33 B3GALT6 PPP4R2 DSCR9 NPY1R ZCWPW2 SNRPA1 C1orf200 ZKSCAN7 VPS37D

Supplemental data S2. GO analysis on PN/NN comparison with SAG Fold GO biological process complete Enrichment P-value establishment of skin barrier (GO:0061436) 39.66 4.16E-07 DNA integration (GO:0015074) 37.58 6.34E-07 regulation of water loss via skin (GO:0033561) 35.70 9.47E-07 RNA-dependent DNA biosynthetic process (GO:0006278) 23.62 2.36E-06 regulation of keratinocyte proliferation (GO:0010837) 17.27 1.41E-02 proximal/distal pattern formation (GO:0009954) 16.23 2.01E-02 multicellular organismal water homeostasis (GO:0050891) 14.87 1.96E-05 water homeostasis (GO:0030104) 12.39 1.08E-04 cornification (GO:0070268) 11.36 4.02E-07 regulation of epidermis development (GO:0045682) 10.82 8.57E-03 skin epidermis development (GO:0098773) 9.27 2.65E-02 skin development (GO:0043588) 8.35 1.01E-17 keratinocyte differentiation (GO:0030216) 7.99 8.44E-11 epidermis development (GO:0008544) 7.86 1.84E-17 regulation of epithelial cell differentiation (GO:0030856) 7.26 1.39E-02 epidermal cell differentiation (GO:0009913) 6.91 1.85E-09 keratinization (GO:0031424) 6.37 6.37E-05 cell junction organization (GO:0034330) 5.64 1.74E-02 urogenital system development (GO:0001655) 4.96 7.87E-04 epithelial cell differentiation (GO:0030855) 4.78 2.24E-10 regulation of epithelial cell proliferation (GO:0050678) 4.73 3.53E-03 morphogenesis of an epithelium (GO:0002009) 4.27 6.29E-04 epithelium development (GO:0060429) 4.19 5.62E-14 gland development (GO:0048732) 4.16 2.02E-03 regulation of body fluid levels (GO:0050878) 4.16 1.04E-04 tissue development (GO:0009888) 4.13 7.36E-24 tissue morphogenesis (GO:0048729) 3.94 2.73E-04 negative regulation of cell proliferation (GO:0008285) 3.49 6.68E-04 embryonic morphogenesis (GO:0048598) 3.38 1.26E-02 anatomical structure formation involved in morphogenesis (GO:0048646) 3.38 3.40E-05 response to wounding (GO:0009611) 3.24 4.26E-02 regulation of cellular component movement (GO:0051270) 3.21 3.41E-04 animal organ morphogenesis (GO:0009887) 3.16 1.62E-04 regulation of cell migration (GO:0030334) 3.10 1.00E-02 regulation of cell adhesion (GO:0030155) 3.05 3.61E-02 regulation of cell motility (GO:2000145) 3.01 9.96E-03 positive regulation of cell differentiation (GO:0045597) 2.96 3.04E-03 cell adhesion (GO:0007155) 2.91 8.13E-05 biological adhesion (GO:0022610) 2.90 9.12E-05 regulation of locomotion (GO:0040012) 2.89 1.30E-02 cell death (GO:0008219) 2.86 3.41E-04 positive regulation of developmental process (GO:0051094) 2.80 1.36E-04 programmed cell death (GO:0012501) 2.79 1.53E-03 regulation of cell proliferation (GO:0042127) 2.79 7.83E-07 cellular response to oxygen-containing compound (GO:1901701) 2.77 2.69E-02 anatomical structure morphogenesis (GO:0009653) 2.73 3.90E-09 regulation of cell differentiation (GO:0045595) 2.67 7.96E-06 response to abiotic stimulus (GO:0009628) 2.66 4.32E-03 positive regulation of multicellular organismal process (GO:0051240) 2.63 7.58E-05 cellular response to endogenous stimulus (GO:0071495) 2.62 1.40E-02 embryo development (GO:0009790) 2.62 4.92E-02 animal organ development (GO:0048513) 2.56 2.35E-13 response to endogenous stimulus (GO:0009719) 2.39 6.97E-03 regulation of multicellular organismal development (GO:2000026) 2.34 6.22E-04 cell differentiation (GO:0030154) 2.32 1.48E-11 response to oxygen-containing compound (GO:1901700) 2.31 2.03E-02 cellular developmental process (GO:0048869) 2.29 1.80E-11 regulation of developmental process (GO:0050793) 2.29 1.14E-05 system development (GO:0048731) 2.26 3.41E-14 cell development (GO:0048468) 2.24 3.14E-02 regulation of multicellular organismal process (GO:0051239) 2.22 2.00E-06 multicellular organism development (GO:0007275) 2.21 5.90E-16 anatomical structure development (GO:0048856) 2.17 1.04E-16 developmental process (GO:0032502) 2.10 2.54E-16 single-multicellular organism process (GO:0044707) 2.07 4.40E-16 single-organism developmental process (GO:0044767) 2.06 7.66E-15 regulation of localization (GO:0032879) 1.94 1.07E-02 negative regulation of cellular process (GO:0048523) 1.85 8.21E-06 regulation of cell communication (GO:0010646) 1.84 6.12E-03 positive regulation of cellular process (GO:0048522) 1.82 1.99E-06 regulation of signaling (GO:0023051) 1.81 1.08E-02 positive regulation of biological process (GO:0048518) 1.80 2.05E-07 negative regulation of biological process (GO:0048519) 1.79 1.48E-05 multicellular organismal process (GO:0032501) 1.75 6.80E-10 regulation of response to stimulus (GO:0048583) 1.69 2.84E-02 signal transduction (GO:0007165) 1.67 6.24E-04 single organism signaling (GO:0044700) 1.61 1.48E-03 signaling (GO:0023052) 1.61 1.54E-03 cell communication (GO:0007154) 1.60 1.65E-03 cellular response to stimulus (GO:0051716) 1.50 8.31E-03 single-organism cellular process (GO:0044763) 1.46 2.72E-07 regulation of cellular process (GO:0050794) 1.36 1.31E-04 regulation of biological process (GO:0050789) 1.33 5.08E-04 single-organism process (GO:0044699) 1.30 2.29E-05 biological regulation (GO:0065007) 1.29 3.71E-03 cellular process (GO:0009987) 1.21 3.12E-04 biological_process (GO:0008150) 1.13 1.55E-02 Supplemental data S3. GO analysis on PP/NN comparison with SAG Fold GO biological process complete Enrichment P-value desmosome organization (GO:0002934) 30.22 7.19E-03 keratinocyte proliferation (GO:0043616) 25.18 1.74E-02 establishment of skin barrier (GO:0061436) 23.50 2.47E-04 regulation of water loss via skin (GO:0033561) 21.15 5.01E-04 regulation of keratinocyte proliferation (GO:0010837) 19.50 1.59E-06 epidermis morphogenesis (GO:0048730) 14.10 7.44E-03 cornification (GO:0070268) 13.19 2.01E-15 proximal/distal pattern formation (GO:0009954) 12.82 1.39E-02 intermediate filament cytoskeleton organization (GO:0045104) 12.09 3.89E-03 intermediate filament-based process (GO:0045103) 11.79 4.68E-03 skin epidermis development (GO:0098773) 11.77 5.57E-08 hair follicle development (GO:0001942) 11.28 4.88E-07 hair cycle process (GO:0022405) 10.85 8.08E-07 molting cycle process (GO:0022404) 10.85 8.08E-07 multicellular organismal water homeostasis (GO:0050891) 10.07 7.69E-04 hair cycle (GO:0042633) 9.85 6.44E-07 molting cycle (GO:0042303) 9.85 6.44E-07 skin development (GO:0043588) 9.37 1.10E-33 epidermis development (GO:0008544) 9.31 8.67E-37 epithelial cell proliferation (GO:0050673) 9.14 2.89E-05 keratinocyte differentiation (GO:0030216) 9.02 1.55E-21 water homeostasis (GO:0030104) 8.39 4.00E-03 regulation of epidermis development (GO:0045682) 8.24 1.73E-02 epidermal cell differentiation (GO:0009913) 7.99 3.19E-20 keratinization (GO:0031424) 7.28 2.25E-11 response to cAMP (GO:0051591) 6.72 9.37E-03 regulation of fat cell differentiation (GO:0045598) 5.94 3.01E-02 formation of primary germ layer (GO:0001704) 5.94 3.01E-02 regulation of epithelial cell differentiation (GO:0030856) 5.90 1.17E-02 response to glucocorticoid (GO:0051384) 5.57 7.95E-03 response to corticosteroid (GO:0031960) 5.39 4.51E-03 regulation of response to wounding (GO:1903034) 5.38 1.16E-02 epithelial cell differentiation (GO:0030855) 5.18 1.04E-19 cellular response to acid chemical (GO:0071229) 4.96 2.11E-03 regulation of epithelial cell proliferation (GO:0050678) 4.80 3.91E-06 cell junction organization (GO:0034330) 4.77 8.01E-03 epithelium development (GO:0060429) 4.65 9.92E-28 epithelial cell development (GO:0002064) 4.65 2.47E-02 morphogenesis of an epithelium (GO:0002009) 4.34 2.85E-07 tissue development (GO:0009888) 4.18 2.91E-37 urogenital system development (GO:0001655) 4.15 5.69E-04 response to acid chemical (GO:0001101) 4.05 4.10E-04 tissue morphogenesis (GO:0048729) 3.94 1.65E-07 renal system development (GO:0072001) 3.76 3.65E-02 regulation of lipid metabolic process (GO:0019216) 3.73 2.20E-02 multicellular organismal homeostasis (GO:0048871) 3.68 4.84E-02 regulation of Wnt signaling pathway (GO:0030111) 3.65 1.59E-02 cell-cell signaling by wnt (GO:0198738) 3.60 5.69E-03 Wnt signaling pathway (GO:0016055) 3.60 5.69E-03 response to metal ion (GO:0010038) 3.51 4.94E-02 regulation of body fluid levels (GO:0050878) 3.43 2.09E-04 gland development (GO:0048732) 3.41 4.18E-03 response to peptide (GO:1901652) 3.28 1.35E-02 reproductive structure development (GO:0048608) 3.24 1.70E-02 cellular response to organonitrogen compound (GO:0071417) 3.22 6.21E-03 reproductive system development (GO:0061458) 3.20 2.06E-02 embryonic morphogenesis (GO:0048598) 3.16 6.26E-04 response to organonitrogen compound (GO:0010243) 3.11 5.00E-06 cell surface receptor signaling pathway involved in cell-cell signaling (GO:1905114) 3.11 3.23E-02 response to inorganic substance (GO:0010035) 3.09 2.13E-02 cellular response to oxygen-containing compound (GO:1901701) 3.03 2.17E-06 cellular response to growth factor stimulus (GO:0071363) 3.03 2.94E-02 negative regulation of cell proliferation (GO:0008285) 3.03 3.52E-04 tube development (GO:0035295) 3.01 2.82E-03 positive regulation of cell differentiation (GO:0045597) 3.01 2.78E-06 wound healing (GO:0042060) 2.99 3.63E-02 response to growth factor (GO:0070848) 2.98 2.30E-02 cell death (GO:0008219) 2.96 2.94E-08 response to wounding (GO:0009611) 2.96 6.29E-03 cell-cell adhesion (GO:0098609) 2.93 4.42E-04 regulation of cellular component movement (GO:0051270) 2.92 2.70E-05 cellular response to endogenous stimulus (GO:0071495) 2.90 2.84E-07 programmed cell death (GO:0012501) 2.89 2.94E-07 anatomical structure formation involved in morphogenesis (GO:0048646) 2.88 4.03E-05 cellular response to nitrogen compound (GO:1901699) 2.87 2.76E-02 regulation of cell proliferation (GO:0042127) 2.83 8.81E-12 animal organ morphogenesis (GO:0009887) 2.83 2.65E-05 response to nitrogen compound (GO:1901698) 2.81 5.14E-05 regulation of cell migration (GO:0030334) 2.80 1.99E-03 cell adhesion (GO:0007155) 2.79 3.86E-07 regulation of cell projection organization (GO:0031344) 2.78 1.97E-02 biological adhesion (GO:0022610) 2.78 4.52E-07 regulation of cell motility (GO:2000145) 2.77 1.02E-03 response to hormone (GO:0009725) 2.77 6.80E-04 positive regulation of developmental process (GO:0051094) 2.77 1.36E-07 response to lipid (GO:0033993) 2.74 3.77E-04 response to endogenous stimulus (GO:0009719) 2.71 8.07E-09 embryo development (GO:0009790) 2.69 1.07E-04 regulation of cell differentiation (GO:0045595) 2.67 9.36E-10 regulation of cell adhesion (GO:0030155) 2.63 3.67E-02 regulation of locomotion (GO:0040012) 2.63 2.24E-03 response to oxygen-containing compound (GO:1901700) 2.61 8.79E-08 regulation of neurogenesis (GO:0050767) 2.61 1.91E-02 anatomical structure morphogenesis (GO:0009653) 2.59 3.14E-12 animal organ development (GO:0048513) 2.55 1.63E-20 regulation of nervous system development (GO:0051960) 2.55 9.81E-03 regulation of response to external stimulus (GO:0032101) 2.55 3.15E-02 negative regulation of signal transduction (GO:0009968) 2.42 6.23E-04 negative regulation of response to stimulus (GO:0048585) 2.40 1.54E-05 negative regulation of cell communication (GO:0010648) 2.38 3.43E-04 response to organic cyclic compound (GO:0014070) 2.38 3.03E-02 negative regulation of signaling (GO:0023057) 2.37 3.79E-04 response to abiotic stimulus (GO:0009628) 2.31 5.95E-03 cellular response to organic substance (GO:0071310) 2.30 1.22E-07 cell differentiation (GO:0030154) 2.26 1.81E-16 positive regulation of multicellular organismal process (GO:0051240) 2.25 2.74E-04 cellular response to chemical stimulus (GO:0070887) 2.24 3.32E-09 cellular developmental process (GO:0048869) 2.23 3.97E-16 regulation of developmental process (GO:0050793) 2.22 2.39E-08 system development (GO:0048731) 2.19 1.80E-19 regulation of multicellular organismal development (GO:2000026) 2.15 1.05E-04 multicellular organism development (GO:0007275) 2.13 1.25E-21 anatomical structure development (GO:0048856) 2.11 2.73E-23 cell development (GO:0048468) 2.09 4.77E-03 response to organic substance (GO:0010033) 2.08 1.30E-07 developmental process (GO:0032502) 2.07 7.80E-24 single-organism developmental process (GO:0044767) 2.05 3.69E-22 single-multicellular organism process (GO:0044707) 2.03 9.73E-23 regulation of localization (GO:0032879) 2.02 2.59E-06 regulation of multicellular organismal process (GO:0051239) 2.00 9.37E-07 regulation of programmed cell death (GO:0043067) 2.00 4.46E-02 neurogenesis (GO:0022008) 1.99 3.04E-02 response to external stimulus (GO:0009605) 1.92 1.79E-02 cell surface receptor signaling pathway (GO:0007166) 1.91 7.55E-04 regulation of cell communication (GO:0010646) 1.82 3.92E-05 positive regulation of cellular process (GO:0048522) 1.82 1.10E-10 nervous system development (GO:0007399) 1.81 1.27E-02 regulation of signaling (GO:0023051) 1.81 4.16E-05 regulation of signal transduction (GO:0009966) 1.80 6.10E-04 negative regulation of biological process (GO:0048519) 1.78 5.27E-09 positive regulation of macromolecule metabolic process (GO:0010604) 1.77 1.16E-03 regulation of cellular protein metabolic process (GO:0032268) 1.76 1.79E-02 positive regulation of cellular metabolic process (GO:0031325) 1.76 1.23E-03 negative regulation of cellular process (GO:0048523) 1.76 1.51E-07 positive regulation of metabolic process (GO:0009893) 1.75 5.74E-04 multicellular organismal process (GO:0032501) 1.75 6.43E-16 regulation of biological quality (GO:0065008) 1.73 6.14E-05 regulation of protein metabolic process (GO:0051246) 1.71 3.02E-02 positive regulation of biological process (GO:0048518) 1.71 3.10E-09 regulation of molecular function (GO:0065009) 1.68 1.22E-02 response to chemical (GO:0042221) 1.67 1.64E-04 regulation of response to stimulus (GO:0048583) 1.67 4.30E-04 response to stress (GO:0006950) 1.65 7.29E-03 cell communication (GO:0007154) 1.60 2.19E-06 signal transduction (GO:0007165) 1.60 2.96E-05 single organism signaling (GO:0044700) 1.56 4.32E-05 signaling (GO:0023052) 1.56 4.54E-05 cellular response to stimulus (GO:0051716) 1.54 2.72E-06 regulation of primary metabolic process (GO:0080090) 1.48 6.47E-04 regulation of macromolecule metabolic process (GO:0060255) 1.48 6.61E-04 regulation of cellular metabolic process (GO:0031323) 1.47 9.44E-04 regulation of metabolic process (GO:0019222) 1.46 4.92E-04 single-organism cellular process (GO:0044763) 1.43 2.82E-10 response to stimulus (GO:0050896) 1.41 4.39E-05 regulation of cellular process (GO:0050794) 1.35 2.36E-07 single-organism process (GO:0044699) 1.32 2.31E-10 biological regulation (GO:0065007) 1.31 3.31E-07 regulation of biological process (GO:0050789) 1.31 6.26E-06 cellular process (GO:0009987) 1.20 8.88E-06 biological_process (GO:0008150) 1.12 3.91E-04

Supplemental data S4. Psoriasis risk-associated genes SLC45A1 NFKBIA IL28RA PRM3 RUNX3 PRSS53 IL23R NOS2 LRRC7 PTRF LCE3B CARD14 FLJ16341 POL1 B3GNT2 TYK2 KCNH7 ILF3 PLCL2 RNF114 NFKBIZ UBE2L3 PTGER4 CARD6 ERAP1 AKAP13 IL13 FUBP1 TNIP1 FASLG IL12B IKBKE EXOC2 ZNF365 HLA‐B PTEN TRAF3IP2 CHUK TNFAIP3 CFL1 TAGAP KLRK1 ELMO1 BRAP DDX58 IL31 KLF4 UBAC2 CAMK2G RP11-61O1.1 ZMIZ1 KLF13 RPS6KA4 TRIM47 ZC3H12C PTPN2 ETS1 FUT2 STAT2

a b Hypermethylated sites Hypomethylated sites

PP PN PP NN PP PN PP NN -log10 p-value

0 5 10 15 PN NN PN NN 100% 50% 0% 50% 100% hypomethylation hypermethylation c

Figure 1 a

Psoriasis involved 1

Psoriasis involved 2

Psoriasis involved 3

Psoriasis uninvolved 1

Psoriasis uninvolved 2

Psoriasis uninvolved 3

Control 1

Control 2

Control 3

Control 4

Control 5

Control 6 b

Psoriasis involved 1

Psoriasis involved 2

Psoriasis involved 3

Psoriasis uninvolved 1

Control 1

Control 2

Control 3

Psoriasis uninvolved 3

Psoriasis uninvolved 2

Figure 2