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Coactivator condensation at super-enhancers links phase separation and gene control

ABSTRACT: Coactivator condensation at super-enhancers links phase separation and gene control

PROVIDER: PRJNA449064 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6955451.fastq.gz	Fastqsanger.gz
	SRR6955442.fastq.gz	Fastqsanger.gz
	SRR6955452.fastq.gz	Fastqsanger.gz
	SRR6955443.fastq.gz	Fastqsanger.gz
	SRR6955444.fastq.gz	Fastqsanger.gz

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Coactivator condensation at super-enhancers links phase separation and gene control (RNA-Seq)

Project description:Coactivator condensation at super-enhancers links phase separation and gene control (RNA-Seq)

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Coactivator condensation at super-enhancers links phase separation and gene control (ChIP-Seq)

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Coactivator condensation at super-enhancers links phase separation and gene control (RNA-Seq)

Project description: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. We recently proposed that a phase-separated multi-molecular assembly underlies the formation and function of SEs. Here, we demonstrate that the SE-enriched factors BRD4 and MED1 form nuclear puncta that occur at SEs and exhibit properties of liquid-like condensates. Disruption of BRD4 and MED1 puncta by 1,6-hexanediol is accompanied by a loss of BRD4 and MED1 at SEs and a loss of RNAPII from SE-driven genes. We find that the intrinsically disordered regions (IDRs) of BRD4 and MED1 are sufficient to form phase-separated droplets in vitro and the MED1 IDR promotes phase separation in living cells. The MED1 IDR droplets are capable of compartmentalizing BRD4 and other transcriptional machinery in nuclear extracts. These results support the idea that SEs form phase-separated condensates that compartmentalize the transcription apparatus at key genes, provide insights into the role of cofactor IDRs in this process, and offer new insights into mechanisms involved in control of key cell identity genes.

2018-04-07 | GSE112807 | GEO

Coactivator condensation at super-enhancers links phase separation and gene control (ChIP-Seq)

2018-04-07 | GSE112806 | GEO

Coactivator condensation at super-enhancers links phase separation and gene control.

Project description:Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the 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 the 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 the control of key cell-identity genes.

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Coactivator condensation drives lineage specification

Project description:Coactivator condensation drives lineage specification

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Coactivator condensation drives cell lineage specification

Project description:Coactivator condensation drives cell lineage specification

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Coactivator condensation at super-enhancers links phase separation and gene control

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-04-07 | GSE112808 | GEO

Co-condensation between transcription factor and coactivator p300 modulates transcriptional bursting kinetics

Project description:The coactivator p300/CBP regulates genes by facilitating the assembly of transcriptional machinery and by acetylating histones and other factors. However, it remains mostly unclear how both functions of p300 are dynamically coordinated during gene control. Here, we showed that p300 appears to orchestrate two functions through the formation of dynamic co-condensates with certain transcription factors (TFs), which is mediated by the interactions between the TF’s trans-activation domain (TAD) and the intrinsically disordered regions (IDRs) of p300. Co-condensation enables spatially defined, all-or-none activation of p300’s catalytic activity, priming the recruitment of other coactivators including Brd4. We further revealed that co-condensation modulates transcriptional initiation rate and burst duration of target genes, underlying nonlinear and cooperative gene regulatory functions. Intriguingly, such modulation is consistent with how p300 shapes transcriptional bursting kinetics globally. Together, complementary lines of evidence suggest a new p300-mediated gene control mechanism, where TF and p300 co-condensation contributes to transcriptional bursting regulation and cooperative gene control.

2022-02-28 | GSE161958 | GEO

Coactivator condensation drives lineage specification

Project description:During development, cells make switch-like decisions to activate the expression of new gene programs leading to lineage specification1. The mechanisms underlying these decisive choices remain unclear2. Here we find that Myocardin (MYOCD), a cardiomyocyte and smooth muscle cell-specific transcriptional coactivator3-6, activates lineage-specific gene programs by concentration-dependent and switch-like formation of nuclear condensates. While compartmentalization of the transcriptional machinery by condensates has been associated with gene activation7,8, directly linking the two processes has been a major challenge for the field9,10. By modeling the natural changes in MYOCD concentration during development, coupled with quantitative fluorescence microscopy, single-cell resolution reporter assays, and cellular differentiation assays, we demonstrate that condensate formation is directly linked to transcriptional activation and lineage specification. During cardiomyocyte and smooth muscle cell differentiation, the formation of MYOCD condensates precedes activation of cell identity genes and these condensates are present at sites of cell identity gene transcription. MYOCD condensates form, activate gene expression, and specify cell state at critical concentration thresholds, dependent upon the C-terminal disordered region of MYOCD. Disrupting condensate formation by manipulating the sequence of this region impairs gene activation which can be rescued by replacing this region with condensate-forming disordered regions from functionally unrelated proteins. These results demonstrate that coactivator condensation at critical concentrations enables switch-like changes in gene expression programs crucial for lineage specification.

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