Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Boija, Ann; Klein, I.; Sabari, Benjamin R.; Dall’Agnese, Alessandra; Coffey, Eliot L.; Zamudio, Alicia V.; Li, Charles; Shrinivas, Krishna; Manteiga, John C.; Hannett, Nancy M.; Abraham, Brian J.; Afeyan, Lena K.; Guo, Yang; Rimel, Jenna K.; Fant, Charli B.; Schuijers, Jurian; Lee, Tong Ihn; Taatjes, Dylan J.; Young, Richard A.

doi:10.1016/j.cell.2018.10.042

Cited by 1,372 publications

(1,483 citation statements)

References 94 publications

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“…Oct4, p53, Myc, nanog, Sox2, RARa, GATA-2 and ER) are seen to colocalize with Mediator in aggregates or droplets in vitro and in cultured cells(Boija et al, 2018). The number and size of Mediator clusters and their presence at regulated enhancers is affected by the presence or absence of specific TFs, suggesting that the capability of TFs to drive cluster formation, of Mediator and/or PolII, could be a key factor for promoting transcription.…”

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confidence: 94%

Decoding the Notch signal

Falo‐Sanjuan

Bray

2019

Dev Growth Differ

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Notch signalling controls many key cellular processes which differ according to the context where the pathway is deployed due to the transcriptional activation of specific sets of genes. The pathway is unusual in its lack of amplification, also raising the question of how it can efficiently activate transcription with limited amounts of nuclear activity. Here, we focus on mechanisms that enable Notch to produce appropriate transcriptional responses and speculate on models that could explain the current gaps in knowledge.

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confidence: 94%

Decoding the Notch signal

Falo‐Sanjuan

Bray

2019

Dev Growth Differ

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“…Such interactions retain a larger conformational flexibility compared to interactions through complementary protein domain surfaces and induced fit (Aguzzi & Altmeyer, 2016;Boeynaems et al, 2018). Moreover, phase separation occurs at gene promoters and super-enhancers (Boehning et al, 2018;Boija et al, 2018;Lu et al, 2018;Sabari et al, 2018). Moreover, phase separation occurs at gene promoters and super-enhancers (Boehning et al, 2018;Boija et al, 2018;Lu et al, 2018;Sabari et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Phase separation of 53 BP 1 determines liquid‐like behavior of DNA repair compartments

et al. 2019

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The DNA damage response (DDR) generates transient repair compartments to concentrate repair proteins and activate signaling factors. The physicochemical properties of these spatially confined compartments and their function remain poorly understood. Here, we establish, based on live cell microscopy and CRISPR/Cas9‐mediated endogenous protein tagging, that 53BP1‐marked repair compartments are dynamic, show droplet‐like behavior, and undergo frequent fusion and fission events. 53BP1 assembly, but not the upstream accumulation of γH2AX and MDC1, is highly sensitive to changes in osmotic pressure, temperature, salt concentration and to disruption of hydrophobic interactions. Phase separation of 53BP1 is substantiated by optoDroplet experiments, which further allowed dissection of the 53BP1 sequence elements that cooperate for light‐induced clustering. Moreover, we found the tumor suppressor protein p53 to be enriched within 53BP1 optoDroplets, and conditions that disrupt 53BP1 phase separation impair 53BP1‐dependent induction of p53 and diminish p53 target gene expression. We thus suggest that 53BP1 phase separation integrates localized DNA damage recognition and repair factor assembly with global p53‐dependent gene activation and cell fate decisions.

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“…The MED1 nuclear bodies show rapid recovery of fluorescence after photobleaching and the large intrinsically disordered regions of MED1 form phase‐separated liquid droplets in vitro, suggesting that MED1 may contribute to the compartmentalization and concentration of biochemical reactions associated with transcription . Diverse transcription factors may thus interact with subunits of Mediator through the phase‐separating capacity of their intrinsically disordered activation domains, leading to gene activation . Such a general mechanism also could apply to the interactions of TR with MED1 through the helix 12 activation domain.…”

Section: Discussionmentioning

confidence: 99%

Mediator subunit MED1 modulates intranuclear dynamics of the thyroid hormone receptor

Femia

Evans

Zhang

et al. 2019

J of Cellular Biochemistry

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The thyroid hormone receptors (TRs) mediate thyroid hormone (T3)‐dependent gene expression. The nuclear import and export signals that direct TR shuttling are well characterized, but little is known about factors modulating nuclear retention. We used fluorescence‐based nucleocytoplasmic scoring and fluorescence recovery after photobleaching in transfected cells to investigate whether Mediator subunits MED1 and MED13 play a role in nuclear retention of TR. When MED1 was overexpressed, there was a striking shift towards a greater nuclear localization of TRβ1 and the oncoprotein v‐ErbA, subtypes with cytosolic populations at steady‐state, and TRβ1 intranuclear mobility was reduced. For TRα1, there was no observable change in its predominantly nuclear distribution pattern or mobility. Consistent with a role for MED1 in nuclear retention, the cytosolic TRα1 and TRβ1 population were significantly greater in MED1−/− cells, compared with MED1+/+ cells. Exposure to T3 and epidermal growth factor, which induces MED1 phosphorylation, also altered TR intranuclear dynamics. Overexpression of miR‐208a, which downregulates MED13, led to a more cytosolic distribution of nuclear‐localized TRα1; however, overexpression of MED13 had no effect on TRβ1 localization. The known binding site of MED1 overlaps with a transactivation domain and nuclear export signal in helix 12 of TR's ligand‐binding domain (LBD). Coimmunoprecipitation assays demonstrated that TR's LBD interacts directly with exportins 5 and 7, suggesting that binding of exportins and MED1 to TR may be mutually exclusive. Collectively, our data provide evidence that MED1 promotes nuclear retention of TR, and highlight the dual functionality of helix 12 in TR transactivation and nuclear export.

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Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Cited by 1,372 publications

References 94 publications

Decoding the Notch signal

Decoding the Notch signal

Phase separation of 53 BP 1 determines liquid‐like behavior of DNA repair compartments

Mediator subunit MED1 modulates intranuclear dynamics of the thyroid hormone receptor

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