DOCSLIB.ORG

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
MYC—Master Regulator of the Cancer Epigenome and Transcriptome G C A T T A C G G C A T genes Review MYC—Master Regulator of the Cancer Epigenome and Transcriptome Candace J. Poole and Jan van Riggelen * Augusta University, Department of Biochemistry and Molecular Biology, 1410 Laney-Walker Blvd., Augusta, GA 30912, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-706-721-0856; Fax: +1-706-721-6608 Academic Editor: Frank Buchholz Received: 28 February 2017; Accepted: 10 May 2017; Published: 13 May 2017 Abstract: Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. However, MYC’s influence on many of these target genes is rather modest and there is little overlap between MYC regulated genes in different cell types, leaving many mechanistic questions unanswered. Recent advances in the field challenge the dogma further, revealing a role for MYC that extends beyond the traditional concept of a sequence-specific transcription factor. In this article, we review MYC’s function as a regulator of the cancer epigenome and transcriptome. We outline our current understanding of how MYC regulates chromatin structure in both a site-specific and genome-wide fashion, and highlight the implications for therapeutic strategies for cancers with high MYC expression. Keywords: MYC; chromatin remodeling; cancer 1. Introduction The importance of MYC in human development and disease has generated intense research interest over the past 30 years, resulting in numerous original articles and reviews (for example, see [1–3]). The MYC family is comprised of c-MYC (herein referred to as MYC, unless otherwise specified), N-MYC, and L-MYC, which encode for basic helix–loop–helix leucine zipper (bHLH-Zip) transcription factors [4] that have been found to play a unique role in regulating an extensive range of biological processes including stemness, cellular proliferation, and neoplastic transformation. While the activity of MYC family members is tightly regulated in non-malignant cells, their constitutive expression is directly linked to the pathogenesis of a wide variety of human cancers [5–8]. The fact that elevated levels of MYC proteins are found in 60–70% of all cancers (reviewed in [1]) and the discovery that tumors can be dependent on continuous MYC expression (known as oncogene addiction) [9] have made this family of oncogenes a highly promising therapeutic target. However, even after three decades of research, both the exact molecular mechanism of how MYC promotes tumorigenesis and a pharmacologic inhibitor selectively targeting the oncogene remain elusive. MYC exerts its neoplastic features by increasing autonomous cellular proliferation, growth, angiogenesis, and genomic destabilization while blocking differentiation (see Figure1) (reviewed in [10]). However, these diverse cellular functions are attributed to the still not completely understood ability of MYC to control the expression of a large set of genes. MYC proteins have first been described as sequence-specific transcription factors, forming heterodimeric complexes with MYC-Associated Factor X (MAX). MYC–MAX complexes are now known to recognize a consensus sequence known as Enhancer box (“E-box”), activating the transcription of genes [11–13]. This finding sparked a comprehensive search for MYC target genes and their function and involvement in neoplastic transformation [14]. However, the scope and complexity of MYC’s action became apparent when Genes 2017, 8, 142; doi:10.3390/genes8050142 www.mdpi.com/journal/genes Genes 2017, 8, 142 2 of 28 Genes 2017, 8, 142 2 of 28 neoplastic transformation [14]. However, the scope and complexity of MYC’s action became apparent whenit was it discovered was discovered that there that arethere approximately are approximately 20,000 20,000 E-box sitesE-box in sites the humanin the human genome, genome, of which of whichonly a only subset a issubset differentially is differentially bound bybound MYC by in MYC a cell in type-specific a cell type- fashionspecific [fashion15]. To further[15]. To increase further increasethe complexity, the complexity, MYC was MYC also was later also found later to found be capable to be capable of repressing of repressing the transcription the transcription of genes of genesthrough through interactions interactions with other with transcription other transcription factors [16factors–18]. It[16 turned–18]. It out turned thatboth out MYC’sthat both activating MYC’s activatingand repressing and repressing functions arefunctions critical are for critical tumorigenesis for tumorigenesis and depend and on depend the recruitment on the recruitment of chromatin of chromatinmodifying modifying co-factors thatco-factors remodel that chromatin remodel chromatin structurein structure the vicinity in the of vicinity the binding of the sites. binding However, sites. However,MYC acts ratherMYC acts weakly rather at manyweakly of itsat many target of gene its promoters,target gene andpromoters, even genomic and even location genomic profiles location have profilesoften proven have non-predictive often proven ofnon MYC-dependent-predictive of transcriptionalMYC-dependent regulation transcriptional [15]. Furthermore, regulation despite [15]. Fconsiderableurthermore, effortsdespite to considerable identify a MYC efforts target to identify gene signature a MYC target using gene comparative signature geneusing profilingcomparative and genegenomic profiling location and analyses, genomic little location overlap analyses, between MYClittle regulatedoverlap genesbetween in differentMYC regulated cell types genes has been in differentfound [14 cell,19]. types To explain has been these found discrepancies, [14,19]. To the explain classic mechanistic these discrepancies, model has the recently classic been mechanistic extended modelto incorporate has recently MYC’s been function extended as a to regulator incorporate of global MYC’s chromatin function structureas a regulator and transcription.of global chromatin In this structurearticle, we and review transcription. the role of In MYC this article, as a regulator we review of the the cancer role of epigenome MYC as a andregulator transcriptome of the cancer both epigenomethrough site-specific, and transcr localiptome mechanisms both through as well site as-specific, genome-wide local mechanisms effects, and highlight as well as the genome potential-wide for effectsnovel therapeutic, and highlight strategies. the potential for novel therapeutic strategies. Figure 1. 1. MYCMYC as asa transcription a transcription factor factor and andoncogene. oncogene. Display Display of the X of-ray the crystal X-ray structure crystal structure of a MYC of– MAXa MYC–MAX heterodimer heterodimer bound boundto DNA to DNAas a assite a site-specific-specific transcription transcription factor factor complex complex [20,21] [20,21].. Overexpression of MYC causes the deregulation of central cellular processes including cell cycle progression, metabolism, differentiation, differentiation, and and angiogenesis angiogenesis,, together together contributi contributingng to neoplastic transformation.transformation. Deregulated Deregulated MYC MYC expression expression is is implicated implicated in in a a wide wide variety variety of of human human cancer cancer types types includingincluding Burkitt’sBurkitt’s lymphoma, lymphoma, acute acute lymphoblastic lymphoblastic leukemia leukemia (ALL), (ALL) and, neuroblastoma. and neuroblastoma. Image createdImage createdwith: UCSF with: Chimera; UCSF Chimera; PDB: 1NKP. PDB: 1NKP. 2. Recruitme Recruitmentnt of Chromatin Modifiers Modifiers for MYC-DependentMYC-Dependent Transactivation The gene gene-specific-specific transactivation model model depends depends on on the ability of MYC MYC–MAX–MAX complexes to recruit chromatin chromatin-modifying-modifying co co-factors.-factors. These These change change the the chromatin chromatin structure structure in the in thevicinity vicinity of the of bindingthe binding site, site,allowing allowing or preventing or preventing the thetranscription transcription of the of thecorresponding corresponding gene gene by regulating by regulating its accessibilityits accessibility to the to basal the basal transcriptional transcriptional machinery machinery or releasing or releasing preloaded preloaded RNA Polymerase RNA Polymerase II (RNA II Pol(RNA II) Polfrom II) pausing. from pausing. An increasing number of chromatin modifying co co-factors-factors including chromatin chromatin “writers “writers”,,” “readers”,“readers,” andand “erasers” “erasers” have have been been found found to interact to interact directly directly or indirectly or indirectly with MYC–MAX with MYC complexes–MAX complexes(for an overview, (for an seeoverview, Figure 2see). ManyFigure of 2). these Many protein–protein of these protein interactions–protein interactions are facilitated are facilitated through throughMYC’s N-terminus, MYC’s N-terminu which harborss, which the harbors transcriptional the transcriptional activation activation domain (TAD) domain and (TAD) highly and conserved highly conservedsequence elements, sequence known elements, as “MYC known box” as (MB)“MYC 0, box” I, and (MB) II, followed 0, I, and by II, MB followed III and IV by in MB the III central and IV MYC in thedomain central ([22 MYC] and domain reviewed ([22 in] [and23]). reviewed MB I, II, andin [23 III]). are MB essential I, II, and for III all are
Load more

Recommended publications
  • Epidermal Wnt Signalling Regulates Transcriptome Heterogeneity and Proliferative Fate in Neighbouring Cells
    bioRxiv preprint doi: https://doi.org/10.1101/152637; this version posted June 20, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Title: Epidermal Wnt signalling regulates transcriptome heterogeneity and proliferative fate in neighbouring cells Arsham Ghahramani1,2 , Giacomo Donati2,3 , Nicholas M. Luscombe1,4,5,† and Fiona M. Watt2,† 1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, United Kingdom 2King’s College London, Centre for Stem Cells and Regenerative Medicine, 28th 8 Floor, Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, United Kingdom 3Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Torino, Italy 4UCL Genetics Institute, University College London, London WC1E 6BT, United Kingdom 5Okinawa Institute of Science & Technology Graduate University, Okinawa 904-0495, Japan † Correspondence to: [email protected] and [email protected] Abstract: Canonical Wnt/beta-catenin signalling regulates self-renewal and lineage selection within the mouse epidermis. Although the transcriptional response of keratinocytes that receive a Wnt signal is well characterised, little is known about the mechanism by which keratinocytes in proximity to the Wnt- receiving cell are co-opted to undergo a change in cell fate. To address this, we performed single-cell mRNA-Seq on mouse keratinocytes co-cultured with and without the presence of beta-catenin activated neighbouring cells. We identified seven distinct cell states in cultures that had not been exposed to the beta-catenin stimulus and show that the stimulus redistributes wild type subpopulation proportions.
    [Show full text]
  • A Role for Mammalian Sin3 in Permanent Gene Silencing
    Molecular Cell Article A Role for Mammalian Sin3 in Permanent Gene Silencing Chris van Oevelen,1 Jinhua Wang,1 Patrik Asp,1 Qin Yan,2,3 William G. Kaelin, Jr.,2,3 Yuval Kluger,1,* and Brian David Dynlacht1,* 1New York University School of Medicine, NYU Cancer Institute, 522 1st Avenue, New York, NY 10016, USA 2Howard Hughes Medical Institute 3Department of Medical Oncology Dana Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] (B.D.D.), [email protected] (Y.K.) DOI 10.1016/j.molcel.2008.10.015 SUMMARY substoichiometric regulatory proteins, including Swi/Snf-remod- eling proteins, retinoblastoma (RB)-binding protein 2 (RBP2), and The multisubunit Sin3 corepressor complex regu- other proteins (Hayakawa et al., 2007; Nagl et al., 2007; Sif et al., lates gene transcription through deacetylation of nu- 2001). Interestingly, RBP2 was recently shown to be a demethy- cleosomes. However, the full range of Sin3 activities lase specific for di- and trimethylated lysine 4 of histone H3 and targets is not well understood. Here, we have (Christensen et al., 2007; Klose et al., 2007). Thus, the Sin3 investigated genome-wide binding of mouse Sin3 complex provides a versatile platform for chromatin modifying and RBP2 as well as histone modifications and nucle- and remodeling activities. Sin3/Rpd3 corepressor complexes are recruited to promoter osome positioning as a function of myogenic differ- regions via sequence-specific repressors such as Ume6 or entiation. Remarkably, we find that Sin3 complexes Mad in yeast and mammalian cells, respectively, resulting in spread immediately downstream of the transcription localized deacetylation of histones within promoter regions and start site on repressed and transcribed genes during transcriptional silencing (Ayer et al., 1995; Kadosh and Struhl, differentiation.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Chromatin Modification and Disease
    J Med Genet 2000;37:905–915 905 Chromatin modification and disease J Med Genet: first published as 10.1136/jmg.37.12.905 on 1 December 2000. Downloaded from Colin A Johnson “Physicians consider that when they have discov- plexes that bring about histone acetylation (the ered the cause of disease, they have also discovered family of histone acetyltransferases or HAT the method of treating it.” Cicero, Tusculan Dis- coactivators) and deacetylation (the histone putations, III.x.23. deacetylases or HDAC corepressors). This In the last few years, the exciting realisation review will focus on some of the clinical aspects in the field of gene regulation is that transcrip- of this recent work on acetylation and the inti- tion factors can function by recruiting large, mate connection that it is now known to have multiprotein complexes which mediate several with the methylation of cytosine residues in types of chromatin modification and remodel- DNA. A third type of chromatin remodelling is ling events that alter the structure of chroma- the direct physical repositioning or disruption tin. Chromatin structure changes include post- of nucleosomes mediated by a family of DNA translational modifications of histones, DNA dependent ATPases. The connection between methylation, remodelling of the chromatin, and this latter type of remodelling and either the maintenance of a heterochromatic or histone acetylation or DNA methylation is euchromatic state. Most of these events are complicated, but progress is being made. For brought about by enzymatic mechanisms. In example, the NuRD multiprotein complex (see general, the catalytic subunits are only one below, fig 1C) contains histone deacetylase and component of the complexes, with the distribu- chromatin remodelling activities, as well as the tion and localisation of the structural changes methyl DNA binding protein MBD3, which dependent on targeting components.
    [Show full text]
  • Rabbit Mab A
    Revision 1 C 0 2 - t SIN3A (D1B7) Rabbit mAb a e r o t S Orders: 877-616-CELL (2355) [email protected] Support: 877-678-TECH (8324) 1 9 Web: [email protected] 6 www.cellsignal.com 7 # 3 Trask Lane Danvers Massachusetts 01923 USA For Research Use Only. Not For Use In Diagnostic Procedures. Applications: Reactivity: Sensitivity: MW (kDa): Source/Isotype: UniProt ID: Entrez-Gene Id: WB, ChIP H M R Mk Endogenous 145 Rabbit IgG Q96ST3 25942 Product Usage Information nucleosome binding of the complex. The SIN3 complex functions to repress transcription, in part, by deacetylating histones at target gene promoters (3,4). In addition, recent For optimal ChIP results, use 5 μl of antibody and 10 μg of chromatin (approximately 4 x studies have shown that SIN3 is recruited to the coding regions of repressed and active 106 cells) per IP. This antibody has been validated using SimpleChIP® Enzymatic genes, where it deacetylates histones and suppresses spurious transcription by RNA Chromatin IP Kits. polymerase II (3,5). In addition to histone deacetylase activity, the SIN3 complex associates with histone methyltransferase (ESET), histone demethylase Application Dilution (JARID1A/RBP2), ATP-dependent chromatin remodeling (SWI/SNF), methylcytosine dioxygenase (TET1), and O-GlcNAc transferase (OGT) activities, all of which appear to Western Blotting 1:1000 contribute to the regulation of target genes (5-9). The SIN3 complex is critical for proper Chromatin IP 1:100 regulation of embryonic development, cell growth and proliferation, apoptosis, DNA replication, DNA repair, and DNA methylation (imprinting and X-chromosome inactivation) Storage (3,4).
    [Show full text]
  • Stress-Mediated Sin3b Activation Leads to Negative Regulation of Subset of P53 Target Genes
    Biosci. Rep. (2015) / 35 / art:e00234 / doi 10.1042/BSR20150122 Stress-mediated Sin3B activation leads to negative regulation of subset of p53 target genes Rama Kadamb*1, Shilpi Mittal*, Nidhi Bansal* and Daman Saluja*1 *Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India Synopsis Downloaded from http://portlandpress.com/bioscirep/article-pdf/35/4/e00234/476914/bsr035e234.pdf by guest on 24 September 2021 The multiprotein SWI-independent 3 (Sin3)–HDAC (histone deacetylase) corepressor complex mediates gene re- pression through its interaction with DNA-binding factors and recruitment of chromatin-modifying proteins on to the promoters of target gene. Previously, an increased expression of Sin3B and tumour suppressor protein, p53 has been established upon adriamycin treatment. We, now provide evidence that Sin3B expression is significantly up-regulated under variety of stress conditions and this response is not stress-type specific. We observed that Sin3B expression is significantly up-regulated both at transcript and at protein level upon DNA damage induced by bleomycin drug, a radiomimetic agent. This increase in Sin3B expression upon stress is found to be p53-dependent and is associated with enhanced interaction of Sin3B with Ser15 phosphorylated p53. Binding of Sin3–HDAC repressor complex on to the promoters of p53 target genes influences gene regulation by altering histone modifications (H3K9me3 and H3K27me3) at target genes. Furthermore, knockdown of Sin3B by shRNA severely compromises p53-mediated gene repression under stress conditions. Taken together, these results suggest that stress-induced Sin3B activation is p53-dependent and is essential for p53-mediated repression of its selective target genes.
    [Show full text]
  • Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence Anthony J
    Published OnlineFirst August 14, 2017; DOI: 10.1158/0008-5472.CAN-16-3410 Cancer Tumor and Stem Cell Biology Research Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence Anthony J. Bainor1, Fang-Ming Deng2, Yu Wang1, Peng Lee2,4, David J. Cantor1, Susan K. Logan1,3,4, and Gregory David1,3,4 Abstract Distinguishing between indolent and aggressive prostate ade- cinoma. Furthermore, SIN3B was downregulated in human pros- nocarcinoma remains a priority to accurately identify patients tate adenocarcinoma correlating with upregulation of its target who need therapeutic intervention. SIN3B has been implicated in genes. Our results suggest a tumor suppressor function for the initiation of senescence in vitro. Here we show that in a mouse SIN3B that limits prostate adenocarcinoma progression, with model of prostate cancer, SIN3B provides a barrier to malignant potential implications for the use of SIN3B and its target genes progression. SIN3B was required for PTEN-induced cellular senes- as candidate diagnostic markers to distinguish indolent from cence and prevented progression to invasive prostate adenocar- aggressive disease. Cancer Res; 77(19); 1–10. Ó2017 AACR. Introduction damage, activation of oncogenes, or loss of a tumor suppres- sor (5, 6). Senescent cells have been identified in preneoplastic Prostate adenocarcinoma is the second most common cancer lesions of several solid tumor types, including prostatic intrae- type in American men with approximately 230,000 new pithelial neoplasias (PIN), but are rarely found in normal patients diagnosed each year, equating to about 1 in 7 men prostate or prostate adenocarcinoma (7). On the basis of these being diagnosed with prostate adenocarcinoma in his lifetime findings, cellular senescence has been hypothesized to prevent (1).
    [Show full text]
  • Senescence-Associated SIN3B Promotes Inflammation and Pancreatic Cancer Progression
    Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression Maïté Rielland, … , George Miller, Gregory David J Clin Invest. 2014;124(5):2125-2135. https://doi.org/10.1172/JCI72619. Research Article Oncology Pancreatic ductal adenocarcinoma (PDAC) is strikingly resistant to conventional therapeutic approaches. We previously demonstrated that the histone deacetylase–associated protein SIN3B is essential for oncogene-induced senescence in cultured cells. Here, using a mouse model of pancreatic cancer, we have demonstrated that SIN3B is required for activated KRAS-induced senescence in vivo. Surprisingly, impaired senescence as the result of genetic inactivation of Sin3B was associated with delayed PDAC progression and correlated with an impaired inflammatory response. In murine and human pancreatic cells and tissues, levels of SIN3B correlated with KRAS-induced production of IL-1α. Furthermore, evaluation of human pancreatic tissue and cancer cells revealed that Sin3B was decreased in control and PDAC samples, compared with samples from patients with pancreatic inflammation. These results indicate that senescence-associated inflammation positively correlates with PDAC progression and suggest that SIN3B has potential as a therapeutic target for inhibiting inflammation-driven tumorigenesis. Find the latest version: https://jci.me/72619/pdf Research article Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression Maïté Rielland,1 David J. Cantor,1 Richard Graveline,1 Cristina Hajdu,2 Lisa Mara,2 Beatriz de Diego Diaz,1 George Miller,3,4 and Gregory David1,5 1Department of Biochemistry and Molecular Pharmacology, 2Department of Pathology, 3Department of Surgery, 4Department of Cell Biology, and 5New York University (NYU) Cancer Institute, NYU School of Medicine, New York, New York, USA.
    [Show full text]
  • 2Czy Lichtarge Lab 2006
    Pages 1–6 2czy Evolutionary trace report by report maker July 31, 2009 4.3.1 Alistat 5 4.3.2 CE 6 4.3.3 DSSP 6 4.3.4 HSSP 6 4.3.5 LaTex 6 4.3.6 Muscle 6 4.3.7 Pymol 6 4.4 Note about ET Viewer 6 4.5 Citing this work 6 4.6 About report maker 6 4.7 Attachments 6 1 INTRODUCTION From the original Protein Data Bank entry (PDB id 2czy): Title: Solution structure of the nrsf/rest-msin3b pah1 complex Compound: Mol id: 1; molecule: paired amphipathic helix protein sin3b; chain: a; fragment: pah1 domain (residues 31-107); synonym: sin3b, transcriptional corepressor sin3b, histone deacetylase complex subunit sin3b; engineered: yes; mol id: 2; molecule: transcription factor rest (version 3); chain: b; fragment: sin3 interaction domain (residues 43-57); synonym: nrsf/rest; engineered: yes CONTENTS Organism, scientific name: Mus Musculus; 2czy contains a single unique chain 2czyA (77 residues long). 1 Introduction 1 Chain 2czyB is too short (15 residues) to permit statistically signi- ficant analysis, and was treated as a peptide ligand. This is an 2 Chain 2czyA 1 NMR-determined structure – in this report the first model in the file 2.1 Q62141 overview 1 was used. 2.2 Multiple sequence alignment for 2czyA 1 2.3 Residue ranking in 2czyA 2 2 CHAIN 2CZYA 2.4 Top ranking residues in 2czyA and their position on 2.1 Q62141 overview the structure 2 2.4.1 Clustering of residues at 25% coverage. 2 From SwissProt, id Q62141, 100% identical to 2czyA: 2.4.2 Overlap with known functional surfaces at Description: Paired amphipathic helix protein Sin3b (Transcriptio- 25% coverage.
    [Show full text]
  • Identification of Genomic Targets of Krüppel-Like Factor 9 in Mouse Hippocampal
    Identification of Genomic Targets of Krüppel-like Factor 9 in Mouse Hippocampal Neurons: Evidence for a role in modulating peripheral circadian clocks by Joseph R. Knoedler A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Neuroscience) in the University of Michigan 2016 Doctoral Committee: Professor Robert J. Denver, Chair Professor Daniel Goldman Professor Diane Robins Professor Audrey Seasholtz Associate Professor Bing Ye ©Joseph R. Knoedler All Rights Reserved 2016 To my parents, who never once questioned my decision to become the other kind of doctor, And to Lucy, who has pushed me to be a better person from day one. ii Acknowledgements I have a huge number of people to thank for having made it to this point, so in no particular order: -I would like to thank my adviser, Dr. Robert J. Denver, for his guidance, encouragement, and patience over the last seven years; his mentorship has been indispensable for my growth as a scientist -I would also like to thank my committee members, Drs. Audrey Seasholtz, Dan Goldman, Diane Robins and Bing Ye, for their constructive feedback and their willingness to meet in a frequently cold, windowless room across campus from where they work -I am hugely indebted to Pia Bagamasbad and Yasuhiro Kyono for teaching me almost everything I know about molecular biology and bioinformatics, and to Arasakumar Subramani for his tireless work during the home stretch to my dissertation -I am grateful for the Neuroscience Program leadership and staff, in particular
    [Show full text]
  • Supplemental Material For: Screen Identifies Bromodomain Protein
    Supplemental Material for: Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination Fade Gong1,2,6, Li-Ya Chiu1,2,6, Ben Cox1,2, François Aymard3,4, Thomas Clouaire3,4, Justin W. Leung1,2, Michael Cammarata5, Mercedes Perez1,2, Poonam Agarwal1,2, Jennifer S. Brodbelt5, Gaëlle Legube3,4 & Kyle. M. Miller1,2,* 1. Supplemental Materials and Methods 2. Supplemental References 3. Supplemental Figure S1-S10 with legends 4. Supplemental Table S1-S3 with legends 1 Supplemental Materials and Methods Plasmid and siRNA transfections Mammalian expression vectors were transfected into U2OS cells by Hilymax (Dojindo) or Fugene HD (Promega) according to manufacturer’s instructions. The I-SceI expressing vector (pCAG-I-SceI) or control vector (pCAG) were transfected into the U2OS DR-GFP cells by Fugene HD (Promega). For HEK293T cells, transient transfections were carried out with pEI (Polyethylenimine, Sigma). Analyses for transient plasmid transfection were performed 24-48 h after transfection. Transfections for siRNA were carried out with lipofectamine RNAiMax (Invitrogen) following the manufacturer’s instructions. Analyses from siRNA treated cells were performed 48-72 h after transfection. The siRNAs used in this study were: siControl: non-targeting pool (Dharmacon); siZMYND8 #1: SMARTpool (Dharmacon); siZMYND8 #2: GGACUUUCCCCUUUUUAUA (targeting the 3’-UTR region of ZMYND8) (Sigma); siZMYND8 #3: GAACAUAGAUGAAUGAAA (Sigma); siCHD4: CCCAGAAGAGGAUUUGUCA (Sigma), siLSD1: GCCUAGACAUUAAACUGAAUA (Sigma); siTIP60 SMARTpool (Dharmacon); siMOF: GCAAAGACCAUAAGAUUUA (Sigma); siCtIP: GGUAAAACAGGAACGAAUC (Sigma); siLigaseIV: AGGAAGUAUUCUCAGGAAUUA (Sigma). Cloning and plasmids 2 cDNAs of human BRD-containing proteins were cloned into the Gateway entry vector pENTR11 by restriction sites, or pDONR201 by attB recombinant sites.
    [Show full text]
  • BRD1-Mediated Acetylation Promotes Integrin Av Gene Expression Via
    Published OnlineFirst February 16, 2018; DOI: 10.1158/1541-7786.MCR-17-0527 Chromatin, Epigenetics and RNA Regulation Molecular Cancer Research BRD1-Mediated Acetylation Promotes Integrin aV Gene Expression Via Interaction with Sulfatide Qian Qian Cai1, Yi Wei Dong1, Bing Qi1, Xiao-Ting Shao2, Rong Wang1, Zhong Yi Chen1, Bao Mei He2, and Xing Zhong Wu1 Abstract Integrin aV gene expression is often dysregulated in cancers found to induce BRD1, monocytic leukemia zinc finger (MOZ) especially in hepatocellular carcinoma (HCC); however, the and histone acetyltransferase binding to ORC1 (HBO1) acetyl- mechanism of regulation is poorly understood. Here, it is dem- transferase multiprotein complex recruitment to the integrin onstrated that sulfatide activated integrin aV gene transcription, aV promoter, which is responsible for histone H3K9/14 acetyla- through histone H3K9/14 acetylation at the promoter, and high tion. Finally, knockdown of BRD1 limited sulfatide-induced integrin aV expression are closely associated with poor prognosis. H3K9/14 acetylation and occupancy of MOZ or HBO1 on integrin To elucidate the mechanism of regulation of acetylation, sulfa- aV gene promoter. tide-bound proteins were screened by mass spectrometry (MS), and bromodomain containing protein 1 (BRD1) was identified as Implications: This study demonstrates that sulfatide inter- an interacting protein that also colocalized with sulfatide in HCC action with BRD1 mediates acetylation and is important for cells. BRD1 was also formed a complex with Sp1, which was regulation of integrin aV gene expression. Mol Cancer Res; 1–13. recruited to the integrin aV gene promoter. Sulfatide was also Ó2018 AACR. Introduction During tumor progression integrins interact with extracellular matrix molecules such as vitronectin, collagen, or glycolipids to Angiogenesis and metastasis are the major cause of tumor trigger signal transduction involved in cell migration and tumor progression and tumor-related mortality.
    [Show full text]