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

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

doi:10.1016/j.molcel.2022.10.013

Cited by 38 publications

(52 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regardless, our imaging tools create the possibility to test in the future how Gal4 clustering is regulated by other Gal4 interactors in vivo , such as SAGA, TBP or TFIIB 64,66,67 . Moreover, it will be interesting to explore whether such factors co-cluster with Gal4 near target genes, as was observed for Hsf1 condensates 29 . Although the role of heterotypic interactions in Gal4 remains unclear, our data suggests that Gal4 homotypic self-interactions are an important contributor to Gal4 clustering.…”

Section: Discussionmentioning

confidence: 92%

“…Moreover, an important open question is how clustering influences TFs during the different steps of transcription activation 13,21–23 . Clustering and IDR-mediated interactions have been reported to enhance target search (increasing the DNA binding rate) 24–28 , to increase the local concentration of TFs at the promoter (increasing the DNA binding rate), to stabilize TF binding to DNA (decreasing the rate of TF unbinding) 12 , to enable 3D genomic interactions between target genes 29 and to boost transcription activation through enhanced recruitment of cofactors and polymerase molecules 30,20,16,31,32 . In contrast, clustering of synthetic TFs and the oncogenic TF EWS::FLI1 instead inhibit gene expression 33,34 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Transcription factor clusters enable target search but do not contribute to target gene activation

Meeussen

Pomp

Brouwer

et al. 2022

Preprint

View full text Add to dashboard Cite

Many transcription factors (TFs) localize in nuclear clusters of locally increased concentrations, but how TF clustering is regulated and how it influences gene expression is not well understood. Here, we use quantitative microscopy in living cells to study the regulation and function of clustering of the budding yeast TF Gal4 in its endogenous context. Our results show that Gal4 cluster formation is facilitated by, but does not completely depend on DNA binding and intrinsically disordered regions. Gal4 cluster properties are regulated by the Gal4-inhibitor Gal80 and Gal4 concentration. Moreover, we discover that clustering acts as a double-edged sword: self-interactions aid TF recruitment to target genes, but recruited Gal4 molecules that are not DNA-bound do not contribute to, and may even inhibit, transcription activation. We propose that cells need to balance the different effects of TF clustering on target search and transcription activation to facilitate proper gene expression.

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Transcription factor clusters enable target search but do not contribute to target gene activation

Meeussen

Pomp

Brouwer

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…This thermal sensing would induce genome remodelling in somatic secretory gonadal cells (e.g., Sertoli, Leydig or granulosa) prior to sex differentiation, which would be maintained until the commitment of the gonad phenotype. Such thermosensitive chromatin interactions could bring key enhancers and promotors from distant locations into close proximity (as recently proposed for transcriptional condensates in yeast [42] ) to alter gene expression in the gonad developmental pathways. Genes in newly formed compartments would then be directly regulated by this thermosensitive pathway.…”

Section: The Three Dimensions Of Sexmentioning

confidence: 89%

“…[40] However, in plants and yeast, gene expression changes induced by heat stress were coupled with modification to 3D genome structure. [37,41,42] In different Drosophila cells, heat stress induces a redistribution of architectural proteins that modulate TAD boundaries. [43] This chromatin remodelling, coupled with covalent his-tone modifications, promoted new long-range interactions that formed new enhancer-promoter contacts that affected gene expression.…”

Section: Environmental 3d Chromatin Regulationmentioning

confidence: 99%

“…Significantly, recent studies in yeast have proposed that transcriptional condensates can rapidly and reversibly reconfigure the 3D genome in response to environmental conditions. [42] Given the importance of the higher-order chromatin structure in demarcating the limits of gene-regulatory domains, disturbances of this architecture would represent a means for rapid change in gene expression. Shifting TADs or compartment boundaries in response to temperature would expose multiple genes to novel regulatory environments.…”

Section: The Three Dimensions Of Sexmentioning

confidence: 99%

See 1 more Smart Citation

Three dimensions of thermolabile sex determination

et al. 2022

View full text Add to dashboard Cite

The molecular mechanism of temperature-dependent sex determination (TSD) is a long-standing mystery. How is the thermal signal sensed, captured and transduced to regulate key sex genes? Although there is compelling evidence for pathways via which cells capture the temperature signal, there is no known mechanism by which cells transduce those thermal signals to affect gene expression. Here we propose a novel hypothesis we call 3D-TSD (the three dimensions of thermolabile sex determination).We postulate that the genome has capacity to remodel in response to temperature by changing 3D chromatin conformation, perhaps via temperature-sensitive transcriptional condensates. This could rewire enhancer-promoter interactions to alter the expression of key sex-determining genes. This hypothesis can accommodate monogenic or multigenic thermolabile sex-determining systems, and could be combined with upstream thermal sensing and transduction to the epigenome to commit gonadal fate.high-throughput chromosome conformation capture; TAD, topologically associated domain; Pg, progesterone; PRC, polycomb repressive complex.

show abstract

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

et al. 2023

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 38 publications

References 84 publications

Transcription factor clusters enable target search but do not contribute to target gene activation

Transcription factor clusters enable target search but do not contribute to target gene activation

Three dimensions of thermolabile sex determination

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

Contact Info

Product

Resources

About