Master transcription factors Oct4, Sox2, and Nanog bind enhancer elements and recruit Mediator to activate much of the gene expression program of pluripotent embryonic stem cells (ESCs). We report ...here that the ESC master transcription factors form unusual enhancer domains at most genes that control the pluripotent state. These domains, which we call super-enhancers, consist of clusters of enhancers that are densely occupied by the master regulators and Mediator. Super-enhancers differ from typical enhancers in size, transcription factor density and content, ability to activate transcription, and sensitivity to perturbation. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. Super-enhancers thus play key roles in the control of mammalian cell identity.
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► Master transcription factors form “super-enhancers” at key cell identity genes. ► Super-enhancers span large domains and employ a large fraction of Mediator. ► Super-enhancers drive cell-type-specific gene expression programs
Super-enhancers are large enhancer domains at key cell identity genes, differ from typical enhancers, and play key roles in the control of mammalian cell identity.
Chromatin regulators have become attractive targets for cancer therapy, but it is unclear why inhibition of these ubiquitous regulators should have gene-specific effects in tumor cells. Here, we ...investigate how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition of the MYC oncogene in multiple myeloma (MM). BRD4 and Mediator were found to co-occupy thousands of enhancers associated with active genes. They also co-occupied a small set of exceptionally large super-enhancers associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impacted genes with super-enhancers, including MYC. Super-enhancers were found at key oncogenic drivers in many other tumor cells. These observations have implications for the discovery of cancer therapeutics directed at components of super-enhancers in diverse tumor types.
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► BRD4 and Mediator occupy super-enhancers in tumor cells ► Super-enhancers are preferentially affected by BET bromodomain inhibition ► Super-enhancers drive expression of oncogenes in multiple cancers
A small set of super-enhancers associated with oncogenes such as MYC was co-occupied by BRD4 and mediator in multiple myeloma. Inhibition of BRD4 leads to selective repression of these genes.
Elevated expression of the c-Myc transcription factor occurs frequently in human cancers and is associated with tumor aggression and poor clinical outcome. The effect of high levels of c-Myc on ...global gene regulation is poorly understood but is widely thought to involve newly activated or repressed “Myc target genes.” We report here that in tumor cells expressing high levels of c-Myc the transcription factor accumulates in the promoter regions of active genes and causes transcriptional amplification, producing increased levels of transcripts within the cell’s gene expression program. Thus, rather than binding and regulating a new set of genes, c-Myc amplifies the output of the existing gene expression program. These results provide an explanation for the diverse effects of oncogenic c-Myc on gene expression in different tumor cells and suggest that transcriptional amplification reduces rate-limiting constraints for tumor cell growth and proliferation.
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► Oncogenic c-Myc occupies promoters of most active genes in tumor cells ► Oncogenic c-Myc increases RNA levels within cell’s existing gene expression program ► Oncogenic c-Myc is an amplifier, not a specifier, of gene expression in cancer cells
Myc-induced transcriptional amplification, rather than the switching on of “Myc target genes” is important for tumorigenesis, suggesting that therapies targeting the apparatus involved in transcriptional amplification may be useful in the treatment of cancer.
Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is ...poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here, we show that SEs consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer enhanced responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis.
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•Super-enhancers (SEs) consist of clusters of active enhancers•SEs are frequently bound by terminal transcription factors of signaling pathways•SE-driven genes are especially responsive to signaling input•SEs acquired in cancer cells are responsive to oncogenic signaling
How large clusters of enhancers, super-enhancers (SEs), drive key cell identity genes is unclear. Hnisz et al. find that SEs contain constituent enhancers that respond to multiple signaling pathways and enhance responsiveness and sensitivity of pluripotency genes in ESCs or tumor-promoting genes in cancer cells to changes in these pathways.
Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of bromodomain and extra-terminal domain (BET) proteins in DLBCL, ...using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of bromodomain 4 (BRD4) at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease.
•BET inhibition exhibits antitumor efficacy in vitro and in vivo•BRD4 localizes in an asymmetric manner to massively overloaded enhancer regions•Genes with adjacent BRD4-loaded super-enhancers are sensitive to BET inhibition•Cancer dependencies are found among super-enhancer-marked genes
Gene expression analysis is a widely used and powerful method for investigating the transcriptional behavior of biological systems, for classifying cell states in disease, and for many other ...purposes. Recent studies indicate that common assumptions currently embedded in experimental and analytical practices can lead to misinterpretation of global gene expression data. We discuss these assumptions and describe solutions that should minimize erroneous interpretation of gene expression data from multiple analysis platforms.
Heart failure (HF) is driven by the interplay between regulatory transcription factors and dynamic alterations in chromatin structure. Pathologic gene transactivation in HF is associated with ...recruitment of histone acetyl-transferases and local chromatin hyperacetylation. We therefore assessed the role of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to expression of genes that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers as essential effectors of transcriptional pause release during HF pathogenesis and identifies BET coactivator proteins as therapeutic targets in the heart.
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•BET bromodomains coactivate cardiac gene expression programs•BET inhibition blocks pathologic cardiac remodeling in vitro and in vivo•BRD4 occupies active cardiac enhancers and promoters•BET inhibition blocks pathologic transcriptional elongation in the adult heart
Small-molecule inhibition of BET bromodomain proteins that recognize acetylated histones blocks release of paused polymerase at genes induced during cardiac stress. This inhibition protects against heart failure.
A small set of core transcription factors (TFs) dominates control of the gene expression program in embryonic stem cells and other well-studied cellular models. These core TFs collectively regulate ...their own gene expression, thus forming an interconnected auto-regulatory loop that can be considered the core transcriptional regulatory circuitry (CRC) for that cell type. There is limited knowledge of core TFs, and thus models of core regulatory circuitry, for most cell types. We recently discovered that genes encoding known core TFs forming CRCs are driven by super-enhancers, which provides an opportunity to systematically predict CRCs in poorly studied cell types through super-enhancer mapping. Here, we use super-enhancer maps to generate CRC models for 75 human cell and tissue types. These core circuitry models should prove valuable for further investigating cell-type-specific transcriptional regulation in healthy and diseased cells.
People often find truth and meaning in claims that have no regard for truth or empirical evidence. We propose that one reason is that people value connecting and fitting in with others, motivating ...them to seek the common ground of communication and generate explanations for how claims might make sense. This increases the likelihood that people experience empty claims as truthful, meaningful, or even profound. Seven studies (N > 16,000 from the United States and China) support our prediction. People who score higher in collectivism (valuing connection and fitting in) are more likely to find fake news meaningful and believe in pseudoscience (Studies 1 to 3). China-U.S. cross-national comparisons show parallel effects. Relative to people from the United States, Chinese participants are more likely to see meaning in randomly generated vague claims (Study 4). People higher in collectivism are more likely to engage in meaning-making, generating explanations when faced with an empty claim, and having done so, are more likely to find meaning (Study 5). People who momentarily experience themselves as more collectivistic are more likely to see empty claims as meaningful (Study 6). People higher in collectivism are more likely to engage in meaning-making unless there is no common ground to seek (Study 7). We interpret our results as suggesting that conditions that trigger collectivism create fertile territory for the spread of empty claims, including fake news and misinformation.
Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the ...atherogenic inflammatory response, we characterized the dynamics, structure, and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by nuclear factor-kappa B accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer-mediated inflammatory transcription, atherogenic endothelial responses, and atherosclerosis in vivo.
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•Activated NF-κB prompts rapid formation of super enhancers in endothelial cells•Super enhancer-bound BRD4 coactivates inflammatory genes•Redistribution of BRD4 results in eviction from basal super enhancers•BET bromodomain inhibition attenuates atherogenic responses and atherosclerosis
Activation of NF-κB underlies many chronic diseases including atherosclerosis. Brown et al. show that TNFα-mediated activation of NF-κB forms de novo super enhancers in endothelial cells by reallocation of the BET bromodomain protein BRD4 away from basal super enhancers. In a preclinical model of atherosclerosis, BET bromodomain inhibition can suppress atherogenesis.
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