The gene expression programs that establish and maintain specific cell states in humans are controlled by thousands of transcription factors, cofactors, and chromatin regulators. Misregulation of ...these gene expression programs can cause a broad range of diseases. Here, we review recent advances in our understanding of transcriptional regulation and discuss how these have provided new insights into transcriptional misregulation in disease.
Super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that define cell identity. Improved understanding of the roles that super-enhancers play in biology ...would be afforded by knowing the constellation of factors that constitute these domains and by identifying super-enhancers across the spectrum of human cell types. We describe here the population of transcription factors, cofactors, chromatin regulators, and transcription apparatus occupying super-enhancers in embryonic stem cells and evidence that super-enhancers are highly transcribed. We produce a catalog of super-enhancers in a broad range of human cell types and find that super-enhancers associate with genes that control and define the biology of these cells. Interestingly, disease-associated variation is especially enriched in the super-enhancers of disease-relevant cell types. Furthermore, we find that cancer cells generate super-enhancers at oncogenes and other genes important in tumor pathogenesis. Thus, super-enhancers play key roles in human cell identity in health and in disease.
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•Catalog of super-enhancers in 86 human cell and tissue types•Disease-associated sequence variation is enriched in super-enhancers•Cancer cells generate super-enhancers at key tumor pathogenesis genes•Super-enhancers provide biomarkers for disease diagnosis and therapy
Super-enhancers in 86 human cell types have been cataloged. Disease-associated sequence variation is enriched in super-enhancers, and cancer cells generate super-enhancers at key tumor pathogenesis genes.
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.
Transcriptional Addiction in Cancer Bradner, James E.; Hnisz, Denes; Young, Richard A.
Cell,
02/2017, Letnik:
168, Številka:
4
Journal Article
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Cancer arises from genetic alterations that invariably lead to dysregulated transcriptional programs. These dysregulated programs can cause cancer cells to become highly dependent on certain ...regulators of gene expression. Here, we discuss how transcriptional control is disrupted by genetic alterations in cancer cells, why transcriptional dependencies can develop as a consequence of dysregulated programs, and how these dependencies provide opportunities for novel therapeutic interventions in cancer.
Gene dysregulation in cancer cells leads to tumor-specific transcriptional dependencies that can be targeted by a new generation of anti-cancer drugs.
Biomolecular Condensates in the Nucleus Sabari, Benjamin R.; Dall’Agnese, Alessandra; Young, Richard A.
Trends in biochemical sciences (Amsterdam. Regular ed.),
11/2020, Letnik:
45, Številka:
11
Journal Article
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Nuclear processes such as DNA replication, transcription, and RNA processing each depend on the concerted action of many different protein and RNA molecules. How biomolecules with shared functions ...find their way to specific locations has been assumed to occur largely by diffusion-mediated collisions. Recent studies have shown that many nuclear processes occur within condensates that compartmentalize and concentrate the protein and RNA molecules required for each process, typically at specific genomic loci. These condensates have common features and emergent properties that provide the cell with regulatory capabilities beyond canonical molecular regulatory mechanisms. We describe here the shared features of nuclear condensates, the components that produce locus-specific condensates, elements of specificity, and the emerging understanding of mechanisms regulating these compartments.
Most nuclear regulatory processes are compartmentalized in condensates.Components with shared functions partition selectively into specific condensates.Bifunctional proteins with both structured and condensate-promoting domains localize condensates to specific genomic loci.Diverse RNA species and RNA-binding proteins promote formation of specific condensates.Further understanding of condensates may provide new therapeutic opportunities for diseases.
Phase-separated multi-molecular assemblies provide a general regulatory mechanism to compartmentalize biochemical reactions within cells. We propose that a phase separation model explains established ...and recently described features of transcriptional control. These features include the formation of super-enhancers, the sensitivity of super-enhancers to perturbation, the transcriptional bursting patterns of enhancers, and the ability of an enhancer to produce simultaneous activation at multiple genes. This model provides a conceptual framework to further explore principles of gene control in mammals.
A phase separation model for transcription explains key features of transcription and sets enhancers, and especially super-enhancers, into the broad family of membraneless organelles.
Understanding how transcriptional enhancers control over 20,000 protein-coding genes to maintain cell-type-specific gene expression programs in all human cells is a fundamental challenge in ...regulatory biology. Recent studies suggest that gene regulatory elements and their target genes generally occur within insulated neighborhoods, which are chromosomal loop structures formed by the interaction of two DNA sites bound by the CTCF protein and occupied by the cohesin complex. Here, we review evidence that insulated neighborhoods provide for specific enhancer-gene interactions, are essential for both normal gene activation and repression, form a chromosome scaffold that is largely preserved throughout development, and are perturbed by genetic and epigenetic factors in disease. Insulated neighborhoods are a powerful paradigm for gene control that provides new insights into development and disease.
DNA loops, formed by the interaction of two CTCF molecules bound to different sites, are structural and functional units of gene control.
Biomolecular Condensates and Cancer Boija, Ann; Klein, Isaac A.; Young, Richard A.
Cancer cell,
02/2021, Letnik:
39, Številka:
2
Journal Article
Recenzirano
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Malignant transformation is characterized by dysregulation of diverse cellular processes that have been the subject of detailed genetic, biochemical, and structural studies, but only recently has ...evidence emerged that many of these processes occur in the context of biomolecular condensates. Condensates are membrane-less bodies, often formed by liquid-liquid phase separation, that compartmentalize protein and RNA molecules with related functions. New insights from condensate studies portend a profound transformation in our understanding of cellular dysregulation in cancer. Here we summarize key features of biomolecular condensates, note where they have been implicated—or will likely be implicated—in oncogenesis, describe evidence that the pharmacodynamics of cancer therapeutics can be greatly influenced by condensates, and discuss some of the questions that must be addressed to further advance our understanding and treatment of cancer.
Malignant transformation is characterized by dysregulation of diverse cellular processes that have been the subject of detailed genetic, biochemical, and structural studies, but only recently has evidence emerged that many of these processes occur in the context of biomolecular condensates. Condensates are membrane-less bodies, often formed by liquid-liquid phase separation, that compartmentalize protein and RNA molecules with related functions. New insights from condensate studies portend a profound transformation in our understanding of cellular dysregulation in cancer. Here we summarize key features of biomolecular condensates, note where they have been implicated—or will likely be implicated—in oncogenesis, describe evidence that the pharmacodynamics of cancer therapeutics can be greatly influenced by condensates, and discuss some of the questions that must be addressed to further advance our understanding and treatment of cancer.
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.
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