Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes

Whyte, Warren A.; Orlando, David A.; Hnisz, Denes; Abraham, Brian J.; Lin, Charles Y.; Kagey, Michael H.; Rahl, Peter B.; Lee, Tong Ihn; Young, Richard A.

doi:10.1016/j.cell.2013.03.035

Cited by 3,385 publications

(4,873 citation statements)

References 95 publications

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“…References for ChIP‐Seq data sets are in order (left to right): Oct2 in B cells 39, Brn2 after 48 h of its overexpression in MEFs 54, Brn2 in NPCs 54, Brn2 in NPCs 55, and Oct4 in ESCs 72. The upper panel was generated using word searches with IUPAC strings instead of pwms on the same set of ChIPseq peaks as in the lower panel.…”

Section: Resultsmentioning

confidence: 99%

Changing POU dimerization preferences converts Oct6 into a pluripotency inducer

Jerabek

et al. 2016

EMBO Reports

123

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The transcription factor Oct4 is a core component of molecular cocktails inducing pluripotent stem cells (iPSCs), while other members of the POU family cannot replace Oct4 with comparable efficiency. Rather, group III POU factors such as Oct6 induce neural lineages. Here, we sought to identify molecular features determining the differential DNA‐binding and reprogramming activity of Oct4 and Oct6. In enhancers of pluripotency genes, Oct4 cooperates with Sox2 on heterodimeric SoxOct elements. By re‐analyzing ChIP‐Seq data and performing dimerization assays, we found that Oct6 homodimerizes on palindromic OctOct more cooperatively and more stably than Oct4. Using structural and biochemical analyses, we identified a single amino acid directing binding to the respective DNA elements. A change in this amino acid decreases the ability of Oct4 to generate iPSCs, while the reverse mutation in Oct6 does not augment its reprogramming activity. Yet, with two additional amino acid exchanges, Oct6 acquires the ability to generate iPSCs and maintain pluripotency. Together, we demonstrate that cell type‐specific POU factor function is determined by select residues that affect DNA‐dependent dimerization.

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Section: Resultsmentioning

confidence: 99%

Changing POU dimerization preferences converts Oct6 into a pluripotency inducer

Jerabek

et al. 2016

EMBO Reports

123

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“…Super-enhancers (SEs) were called on H4K5K8ac reproducible peaks (IDR >0.01) using the publicly available tool ROSE [16,70] with default parameters. The stitched regions that are not classified as super-enhancers by ROSE are defined as typical enhancers (TEs).…”

Section: Methodsmentioning

confidence: 99%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

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“…© 2017 American Association for Cancer cancerdiscovery.aacrjournals.org Downloaded from www.aacrjournals.org cell identity and disease (35,57). Using ROSE (35), we identified 1,451 superenhancers in the ccRCC cohort, of which 1,157 were gained in tumors and 294 were lost in tumors (Supplementary Table S12).…”

Section: Researchmentioning

confidence: 99%

“…Compared with promoters that are largely cell-type invariant, distal enhancers integrate multiple lineage-and context-dependent signals, catering to the specialized needs of diverse cell types and diseases (32,33). In cancer, such master regulators are frequently located near "superenhancers" or "stretch-enhancers" marked by long stretches of H3K27ac signals (34,35). For example, subtype-specific genomic alterations such as EGFRvIII in glioblastoma (36) and EWS-FLI in Ewing sarcoma (37) induce de novo enhancers, causing reactivation of developmental master regulators required for self-renewal and lineage specification (36 41), the impact of these protein alterations at specific epigenomic loci remains unclear.…”

mentioning

confidence: 99%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

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Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau ( VHL ) tumor suppressor. Roles for noncoding cis -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi ed ZNF395 as a ccRCCspecifi c and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo . VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specifi c driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGnIFICAnCE:Comprehensive epigenomic profi ling of ccRCC establishes a compendium of somatically altered cis -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specifi c promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305.

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Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes

Cited by 3,385 publications

References 95 publications

Changing POU dimerization preferences converts Oct6 into a pluripotency inducer

Changing POU dimerization preferences converts Oct6 into a pluripotency inducer

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

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