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BRD4 O-GlcNAcylation attenuates phase separation to regulate transcription

ABSTRACT: BRD4 undergoes liquid-liquid phase separation (LLPS) at super-enhancers (SEs) to facilitate gene control. However, the regulatory mechanisms and transcriptional consequences of BRD4 condensation remain elusive. Here, we show that the BRD4 C-terminal intrinsically disordered region (IDR) is a primary interacting region for O-GlcNAc transferase (OGT), enabling O-GlcNAc modifications at 12 potential sites. O-GlcNAcylation attenuates BRD4 LLPS, leading to small puncta and increased fluidity, which significantly declines occupancy and transcription at SEs. We further demonstrate that loss of O-GlcNAcylation on BRD4 led to elevated gene expression relating to cell cycle and DNA damage, allowing cells less sensitive to DNA damage and promoting faster growth. Therefore, we identify an O-GlcNAc–mediated regulatory mechanism for BRD4 LLPS that governs gene control at SEs, showcasing how O-GlcNAc modifications can influence transcriptional activities at SEs through a phase separation model.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282031 | GEO | 2026/07/29

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE282031_12A_Ctrl_ChIP_Merged.bw	Other
	GSE282031_12A_siYTHDC1_ChIP_Merged.bw	Other
	GSE282031_Chr_Raw_Count.txt.gz	Txt
	GSE282031_Cyto_Raw_Count.txt.gz	Txt

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O-GlcNAcylation of BRD4 attenuates phase separation to regulate transcription

Project description:BRD4 undergoes liquid-liquid phase separation (LLPS) at super-enhancers (SEs) and confers prominent gene control. However, the regulatory mechanism and transcriptional consequences of BRD4 condensation remain elusive. Here we identified that the C-terminal intrinsic disordered region of BRD4 serves as the primary interacting region with O-GlcNAc transferase (OGT) for O-GlcNAc modifications at 12 possible sites. O-GlcNAcylation attenuates the LLPS propensity of BRD4 with reduced puncta size and increased fluidity. These in turn result in significantly declined occupancy and transcription at SEs. We further demonstrated that loss of O-GlcNAcylation on BRD4 led to elevated gene expression relating to cell cycle and DNA damage, allowing cells less sensitive to DNA damage and grow faster. Therefore, our results demonstrate an O-GlcNAc–mediated regulatory mechanism of BRD4 LLPS for gene control at SEs, showcasing an example of how post-translational modifications regulate transcriptional activities at SEs through a phase separation model.

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