Primordial super-enhancers: heat shock-induced chromatin organization in yeast

Kainth, Amoldeep S.; Chowdhary, Surabhi; Pincus, David; Gross, David S.

doi:10.1016/j.tcb.2021.04.004

Cited by 25 publications

(25 citation statements)

References 78 publications

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“…However, rather than driving transcription of HSR genes, these foci have been shown to localize to noncoding satellite DNA regions and are anti-correlated with HSR gene expression (Gaglia et al, 2020;Jolly et al, 2004). Despite this evidence, it is also clear that mammalian HSR genes are highly induced following heat shock, suggesting that HSF1 is able to recruit large quantities of the transcriptional machinery (Kainth et al, 2021;Mahat et al, 2016). Thus, in addition to the large HSF1 foci localized to noncoding regions, more advanced imaging techniques may reveal smaller HSF1 foci that condense with Mediator at HSR genes to activate transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, in addition to the large HSF1 foci localized to noncoding regions, more advanced imaging techniques may reveal smaller HSF1 foci that condense with Mediator at HSR genes to activate transcription. Moreover, although the organization of mammalian genomes into topologically associated domains (TADs) (Dixon et al, 2012) would seem to preclude the ability of HSR genes to coalesce upon activation like they do in yeast, multiple HSR genes are clustered adjacent to each other in the human genome, potentially allowing intergenic interactions among HSR genes to occur (Kainth et al, 2021). Thus, it is possible that inducible intergenic transcriptional condensates are conserved features of the HSR across the eukaryotic lineage.…”

Section: Discussionmentioning

confidence: 99%

“…HSR genes engage in selective intra-and inter-chromosomal interactions upon heat shock-induced activation (Chowdhary et al, 2017;Chowdhary et al, 2019), and we hypothesized that these interactions are driven by condensate formation (Kainth et al, 2021). Using a highly sensitive chromosome conformation capture technique (TaqI-3C) (Chowdhary et al, 2020), we have demonstrated interactions among seven Hsf1-dependent genes spanning distinct chromosomes (Chowdhary et al, 2019) (Figure 2D).…”

Section: Hsr Condensates Drive Intergenic Interactions Among Hsr Genesmentioning

confidence: 95%

“…Recent studies in budding yeast have revealed profound remodeling of the 3D chromatin architecture following activation of the HSR by Hsf1 (Chowdhary et al, 2017;Chowdhary et al, 2019), and we have hypothesized that transcriptional condensates drive this 3D genomic reorganization (Kainth et al, 2021). Indeed, the HSR shares several key features with mammalian SEs, such as recruitment of high levels of the transcriptional machinery at the associated genes and extensive DNA looping interactions.…”

Section: Introductionmentioning

confidence: 95%

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Inducible transcriptional condensates drive 3D genome reorganization in the heat shock response

Chowdhary

Kainth

Paracha

et al. 2021

Preprint

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SUMMARYMammalian developmental and disease-associated genes concentrate large quantities of the transcriptional machinery by forming membrane-less compartments known as transcriptional condensates. However, it is unknown whether these structures are evolutionarily conserved, capable of stress-inducible gene activation or involved in 3D genome reorganization. Here, we identify inducible transcriptional condensates in the yeast heat shock response (HSR). HSR condensates are biophysically dynamic spatiotemporal clusters of the sequence-specific transcription factor Heat shock factor 1 (Hsf1) with Mediator and RNA Pol II. Uniquely, HSR condensates drive the coalescence of multiple Hsf1 target genes, even those located on different chromosomes. Binding of the chaperone Hsp70 to a site on Hsf1 represses clustering, while an intrinsically disordered region on Hsf1 promotes condensate formation and intergenic interactions. Mutation of both Hsf1 determinants reprograms HSR condensates to become mammalian-like: constitutively active without intergenic coalescence. These results suggest that transcriptional condensates are ancient and flexible compartments of eukaryotic gene control.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Hsr Condensates Drive Intergenic Interactions Among Hsr Genesmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 95%

See 2 more Smart Citations

Inducible transcriptional condensates drive 3D genome reorganization in the heat shock response

Chowdhary

Kainth

Paracha

et al. 2021

Preprint

Self Cite

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“…HSF1 can be rapidly conformationally activated upon proteotoxic stress such as heat shock, after which it regulates chaperone expression (Anckar and Sistonen, 2011;Mahat et al, 2016;Solís et al, 2016). This chaperone regulation by HSF1 according to fluctuating cellular requirements is preserved among eukaryotes (Pincus, 2020;Kainth et al, 2021). The levels of all Hsp90 chaperones are reduced in AD while HSP70 is overproduced (Koopman and Rüdiger, 2020).…”

Section: Transcription Of Trap1 By Hsf1mentioning

confidence: 99%

The Mitochondrial Hsp90 TRAP1 and Alzheimer’s Disease

Dekker

Rüdiger

2021

Front. Mol. Biosci.

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Alzheimer’s Disease (AD) is the most common form of dementia, characterised by intra- and extracellular protein aggregation. In AD, the cellular protein quality control (PQC) system is derailed and fails to prevent the formation of these aggregates. Especially the mitochondrial paralogue of the conserved Hsp90 chaperone class, tumour necrosis factor receptor-associated protein 1 (TRAP1), is strongly downregulated in AD, more than other major PQC factors. Here, we review molecular mechanism and cellular function of TRAP1 and subsequently discuss possible links to AD. TRAP1 is an interesting paradigm for the Hsp90 family, as it chaperones proteins with vital cellular function, despite not being regulated by any of the co-chaperones that drive its cytosolic paralogues. TRAP1 encloses late folding intermediates in a non-active state. Thereby, it is involved in the assembly of the electron transport chain, and it favours the switch from oxidative phosphorylation to glycolysis. Another key function is that it ensures mitochondrial integrity by regulating the mitochondrial pore opening through Cyclophilin D. While it is still unclear whether TRAP1 itself is a driver or a passenger in AD, it might be a guide to identify key factors initiating neurodegeneration.

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The Mediator subunit MED12 promotes formation of HSF1 condensates on heat shock response element arrays in heat‐shocked cells

et al. 2023

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Upon heat shock, activated heat shock transcription factor 1 (HSF1) binds to the heat shock response elements (HSEs) in the promoters of mammalian heat shock protein (HSP)-encoding genes and recruits the preinitiation complex and coactivators, including Mediator. These transcriptional regulators may be concentrated in phase-separated condensates around the promoters, but they are too minute to be characterized in detail. We herein established HSF1 À/À mouse embryonic fibroblasts harbouring HSP72-derived multiple HSE arrays and visualized the condensates of fluorescent protein-tagged HSF1 with liquid-like properties upon heat shock. Using this experimental system, we demonstrate that endogenous MED12, a subunit of Mediator, is concentrated in artificial HSF1 condensates upon heat shock. Furthermore, the knockdown of MED12 markedly reduces the size of condensates, suggesting an important role for MED12 in HSF1 condensate formation.

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Primordial super-enhancers: heat shock-induced chromatin organization in yeast

Cited by 25 publications

References 78 publications

Inducible transcriptional condensates drive 3D genome reorganization in the heat shock response

Inducible transcriptional condensates drive 3D genome reorganization in the heat shock response

The Mitochondrial Hsp90 TRAP1 and Alzheimer’s Disease

The Mediator subunit MED12 promotes formation of HSF1 condensates on heat shock response element arrays in heat‐shocked cells

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