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Emergent 3D genome reorganization from the stepwise assembly of transcriptional condensates

ABSTRACT: Transcriptional condensates are clusters of transcription activators, coactivators, and RNA Pol II associated with high-level gene expression, yet how they are assembled—via concerted or sequential recruitment of constituent biomolecules—is unknown. Here we show that transcriptional condensates form in a stepwise manner to enable precise three-dimensional (3D) gene control. We demonstrate this using a quintessential model of eukaryotic gene regulation—the heat shock response (HSR). In budding yeast, the HSR transcription activator Hsf1 forms clusters upon partially dissociating from the chaperone Hsp70. Next, Hsf1 partitions the coactivator Mediator into clusters following further Hsp70 dissociation and phosphorylation. Pol II clustering constitutes the last step that drives emergent HSR gene coalescence. Separation-of-function mutants reveal a graded HSR transcription rheostat rather than a binary ON/OFF switch, allowing dynamic fine-tuning of HSR gene expression. We provide evidence for a specialized role of Pol II condensates in adaptive 3D genome reconfiguration, beyond gene activation.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE286187 | GEO | 2026/08/31

REPOSITORIES: GEO

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Project description:Heat shock response (HSR) is critical for survival of organisms undergoing proteotoxic stress. Heat shock factor 1 (HSF1) is widely believed to be the master regulator of this response. Here, we examined the kinetics of the transcriptional response and HSF1 binding changes genome-wide after heat shock (HS) with high sensitivity and high spatial and temporal resolution using PRO-seq and ChIP-seq assays respectively in wild type and in hsf1-deletion mouse embryonic fibroblasts. The transcriptional response is rapid, dynamic, and extensive with activation of several hundred genes and repression of several thousands of genes. Although HSF1 is critically required for classical inducible Heat Shock Protein (HSP) genes, it is not required for the majority of gene activation. HSF1 acts mechanistically to promote RNA polymerase II (Pol II) release from the promoter-proximal pause, while recruitment and initiation of Pol II are predominantly HSF1-independent. Surprisingly, a major class of cytoskeleton genes is immediately (within 2.5 minutes) and transiently activated in an HSF1-independent manner. A second wave of regulation is characterized by robust activation or repression of new sets of genes. The broad repression of thousands of genes, a quarter of which are repressed immediately upon HS and the rest are repressed in the second wave of regulation, is mediated at the level of decreasing Pol II pause release and not at prior steps of Pol II recruitment or initiation. Notably, heat shock does not induce transcription of some previously defined HSP genes, and HSF2 â a homolog of HSF1 â does not compensate for the lack of HSF1. Together, these findings indicate that mammalian cells cope with stress by rapidly inducing pervasive and dramatic changes in transcription that are largely modulated at the step of pause release, and only a fraction of this regulation is HSF1-dependent. Examination of transcriptional regulation before and after heat shock in WT, HSF1-/-, and HSF1&2-/- MEFs

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Emergent 3D genome reorganization from the stepwise assembly of transcriptional condensates

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