Coactivator condensation at super-enhancers links phase separation and gene control
Benjamin R. Sabari,Alessandra Dall’Agnese,Ann Boija,Isaac A. Klein,Isaac A. Klein,Eliot L. Coffey,Krishna Shrinivas,Brian J. Abraham,Nancy M. Hannett,Alicia V. Zamudio,John C. Manteiga,Charles H. Li,Yang Eric Guo,Daniel S. Day,Jurian Schuijers,Eliza Vasile,Sohail Malik,Denes Hnisz,Tong Ihn Lee,Ibrahim I Cisse,Robert G. Roeder,Phillip A. Sharp,Arup K. Chakraborty,Richard A. Young +23 more
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TLDR
It is postulated that super-enhancers are phase-separated multimolecular assemblies, also known as biomolecular condensates, which provide a means to compartmentalize and concentrate biochemical reactions within cells.Abstract:
Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here, we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets and MED1-IDR droplets can compartmentalize and concentrate transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in control of key cell identity genes.read more
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Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains.
Ann Boija,Isaac A. Klein,Benjamin R. Sabari,Alessandra Dall’Agnese,Eliot L. Coffey,Alicia V. Zamudio,Charles H. Li,Krishna Shrinivas,John C. Manteiga,Nancy M. Hannett,Brian J. Abraham,Lena K. Afeyan,Yang Eric Guo,Jenna K. Rimel,Charli B. Fant,Jurian Schuijers,Tong Ihn Lee,Dylan J. Taatjes,Richard A. Young +18 more
TL;DR: It is reported that diverse ADs form phase- separated condensates with the Mediator coactivator, suggesting that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensate with Mediation is involved in gene activation.
Journal ArticleDOI
Mediator and RNA polymerase II clusters associate in transcription-dependent condensates
Won-Ki Cho,Jan-Hendrik Spille,Micca Hecht,Choongman Lee,Charles H. Li,Valentin Grube,Valentin Grube,Ibrahim I Cisse +7 more
TL;DR: This work used live-cell superresolution and light-sheet imaging to study the organization and dynamics of the Mediator coactivator and RNA polymerase II (Pol II) directly and suggests that large clusters of Mediator, recruited by transcription factors at large or clustered enhancer elements, interact with large Pol II clusters in transcriptional condensates in vivo.
Journal ArticleDOI
Long-range enhancer-promoter contacts in gene expression control.
TL;DR: The latest understanding of long-range enhancer–promoter crosstalk is discussed, including target-gene specificity, interaction dynamics, protein and RNA architects of interactions, roles of 3D genome organization and the pathological consequences of regulatory rewiring.
Journal ArticleDOI
Organization of Chromatin by Intrinsic and Regulated Phase Separation
Bryan A. Gibson,Lynda K. Doolittle,Maximillian W.G. Schneider,Liv E. Jensen,Nathan Gamarra,Lisa Henry,Daniel W. Gerlich,Sy Redding,Michael K. Rosen +8 more
TL;DR: It is demonstrated that reconstituted chromatin undergoes histone tail-driven liquid-liquid phase separation (LLPS) in physiologic salt and when microinjected into cell nuclei, producing dense and dynamic droplets.
Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes
Jill M. Dowen,Zi Peng Fan,Denes Hnisz,Gang Ren,Brian J. Abraham,Abraham S. Weintraub,Jurian Schuijers,Tong Ihn Lee,Keji Zhao,Lyndon Nuoxi Zhang,Richard A. Young +10 more
TL;DR: In this article, the authors used ESC cohesin ChIA-PET data to identify the local chromosomal structures at both active and repressed genes across the genome and reveal that super-enhancer-driven genes generally occur within chromosome structures that are formed by the looping of two interacting CTCF sites co-occupied by co-hesin.
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