“Structure”-function relationships in eukaryotic transcription factors: The role of intrinsically disordered regions in gene regulation

Ferrie, John J.; Tjian, Robert; Darzacq, Xavier

doi:10.1016/j.molcel.2022.09.021

Cited by 72 publications

(50 citation statements)

References 102 publications

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“…Both these regions have been predicted and shown to contain disordered regions 15,58,59 (Figure S5A). Since IDRs have previously been linked to cluster formation and target search 13,24,25 , we wondered how the CR and AD of Gal4 contribute to cluster formation and localization.…”

Section: Idrs Are Not Essential For Gal4 Clustering But Contribute To...mentioning

confidence: 99%

“…It has been suggested that cluster formation is driven by multivalent interactions between intrinsically disordered regions (IDRs) 4,12,13 . IDRs are enriched in the transactivation domains of many TFs and enable self-interactions (homotypic interactions) and multivalent interactions with IDRs of other components of the transcriptional machinery (heterotypic interactions) 4,11,12,[14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, an important open question is how clustering influences TFs during the different steps of transcription activation 13,[21][22][23] . Clustering and IDR-mediated interactions have been reported to enhance target search (increasing the DNA binding rate) [24][25][26][27][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 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Meeussen

Pomp

Brouwer

et al. 2022

Preprint

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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.

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Section: Idrs Are Not Essential For Gal4 Clustering But Contribute To...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

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“…IDRs can drive protein aggregation and phase transitions, and the poly-Q domain of GAF has been implicated in such functions (Boeynaems et al 2018; Wilkins and Lis 1999; Agianian et al 1999; Ferrie et al 2022). Thus, it is possible that the reduced hatching rate for embryos inheriting the short isoform lacking the poly-Q domain might result from a failure of the mutant GAF protein to concentrate in subnuclear foci.…”

Section: Resultsmentioning

confidence: 99%

“…Several regulatory proteins and transcription factors have been reported to have non-uniform distribution within the nucleus, visualized as foci and referred to as condensates or hubs. In many cases, this distribution is driven by multivalent interactions between the intrinsically disordered regions (IDRs) prevalent in eukaryotic transcription factors (Boeynaems et al 2018; Rippe 2022; Peng et al 2020; Ferrie et al 2022). For example, Heterochromatin Protein 1a/ α (HP1a/ α ) forms membraneless condensates thought to be formed by liquid-liquid phase separation (LLPS) in both flies and mammals (Strom et al 2017; Larson et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Localization of the pioneer factor GAF to subnuclear foci is driven by DNA binding and required to silence satellite repeat expression

Gaskill

Soluri

Branks

et al. 2022

Preprint

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The eukaryotic genome is organized to enable the precise regulation of gene expression required for development. This organization is established during early development when the embryo transitions from a fertilized germ cell to the totipotent zygote. To understand the factors and processes that drive genomic organization, we focused on the pioneer factor GAGA factor (GAF) that is required for early embryonic development in Drosophila. GAF transcriptionally activates the zygotic genome and is localized to subnuclear foci. We show that this non-uniform distribution is driven by binding to the highly abundant GA-satellite repeats. At GA-repeats, GAF is necessary to form heterochromatin and silence transcription. Thus, GAF is required to establish both active and silent regions. We propose that foci formation enables GAF to have opposing transcriptional roles within a single nucleus. Our data support a model in which modulation of the subnuclear concentration of transcription factors acts to organize the nucleus into functionally distinct domains that are essential for the robust regulation of gene expression.

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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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“Structure”-function relationships in eukaryotic transcription factors: The role of intrinsically disordered regions in gene regulation

Cited by 72 publications

References 102 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

Localization of the pioneer factor GAF to subnuclear foci is driven by DNA binding and required to silence satellite repeat expression

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

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