Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes

Alicia V. Zamudio; Alessandra Dall'Agnese; Jonathan E. Henninger; John C. Manteiga; Lena K. Afeyan; Nancy M. Hannett; Eliot L. Coffey; Charles H. Li; Ozgur Oksuz; Benjamin R. Sabari; Ann Boija; Isaac A. Klein; Susana W. Hawken; Jan Hendrik Spille; Tim Michael Decker; Ibrahim I. Cisse; Brian J. Abraham; Tong I. Lee; Dylan J. Taatjes; Jurian Schuijers; Richard A. Young

doi:10.1016/j.molcel.2019.08.016

Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes

Alicia V. Zamudio, Alessandra Dall'Agnese, Jonathan E. Henninger, John C. Manteiga, Lena K. Afeyan, Nancy M. Hannett, Eliot L. Coffey, Charles H. Li, Ozgur Oksuz, Benjamin R. Sabari, Ann Boija, Isaac A. Klein, Susana W. Hawken, Jan Hendrik Spille, Tim Michael Decker, Ibrahim I. Cisse, Brian J. Abraham, Tong I. Lee, Dylan J. Taatjes, Jurian SchuijersRichard A. Young

Research output: Contribution to journal › Article › peer-review

145 Scopus citations

Abstract

The gene expression programs that define the identity of each cell are controlled by master transcription factors (TFs) that bind cell-type-specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here, we present evidence that signaling factors for the WNT, TGF-β, and JAK/STAT pathways use their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator β-catenin interacts both with components of condensates and DNA-binding factors to selectively occupy super-enhancer-associated genes. We propose that the cell-type specificity of the response to signaling is mediated in part by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity.

Original language	English (US)
Pages (from-to)	753-766.e6
Journal	Molecular cell
Volume	76
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2019.08.016
State	Published - Dec 5 2019
Externally published	Yes

Keywords

JAK/STAT
TGF-β
WNT
gene regulation
signaling pathway
transcriptional condensates

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2019.08.016

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Zamudio, A. V., Dall'Agnese, A., Henninger, J. E., Manteiga, J. C., Afeyan, L. K., Hannett, N. M., Coffey, E. L., Li, C. H., Oksuz, O., Sabari, B. R., Boija, A., Klein, I. A., Hawken, S. W., Spille, J. H., Decker, T. M., Cisse, I. I., Abraham, B. J., Lee, T. I., Taatjes, D. J., ... Young, R. A. (2019). Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes. Molecular cell, 76(5), 753-766.e6. https://doi.org/10.1016/j.molcel.2019.08.016

Zamudio, AV, Dall'Agnese, A, Henninger, JE, Manteiga, JC, Afeyan, LK, Hannett, NM, Coffey, EL, Li, CH, Oksuz, O, Sabari, BR, Boija, A, Klein, IA, Hawken, SW, Spille, JH, Decker, TM, Cisse, II, Abraham, BJ, Lee, TI, Taatjes, DJ, Schuijers, J & Young, RA 2019, 'Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes', Molecular cell, vol. 76, no. 5, pp. 753-766.e6. https://doi.org/10.1016/j.molcel.2019.08.016

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title = "Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes",

abstract = "The gene expression programs that define the identity of each cell are controlled by master transcription factors (TFs) that bind cell-type-specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here, we present evidence that signaling factors for the WNT, TGF-β, and JAK/STAT pathways use their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator β-catenin interacts both with components of condensates and DNA-binding factors to selectively occupy super-enhancer-associated genes. We propose that the cell-type specificity of the response to signaling is mediated in part by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity.",

keywords = "JAK/STAT, TGF-β, WNT, gene regulation, signaling pathway, transcriptional condensates",

author = "Zamudio, {Alicia V.} and Alessandra Dall'Agnese and Henninger, {Jonathan E.} and Manteiga, {John C.} and Afeyan, {Lena K.} and Hannett, {Nancy M.} and Coffey, {Eliot L.} and Li, {Charles H.} and Ozgur Oksuz and Sabari, {Benjamin R.} and Ann Boija and Klein, {Isaac A.} and Hawken, {Susana W.} and Spille, {Jan Hendrik} and Decker, {Tim Michael} and Cisse, {Ibrahim I.} and Abraham, {Brian J.} and Lee, {Tong I.} and Taatjes, {Dylan J.} and Jurian Schuijers and Young, {Richard A.}",

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year = "2019",

month = dec,

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doi = "10.1016/j.molcel.2019.08.016",

language = "English (US)",

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T1 - Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes

AU - Zamudio, Alicia V.

AU - Dall'Agnese, Alessandra

AU - Henninger, Jonathan E.

AU - Manteiga, John C.

AU - Afeyan, Lena K.

AU - Hannett, Nancy M.

AU - Coffey, Eliot L.

AU - Li, Charles H.

AU - Oksuz, Ozgur

AU - Sabari, Benjamin R.

AU - Boija, Ann

AU - Klein, Isaac A.

AU - Hawken, Susana W.

AU - Spille, Jan Hendrik

AU - Decker, Tim Michael

AU - Cisse, Ibrahim I.

AU - Abraham, Brian J.

AU - Lee, Tong I.

AU - Taatjes, Dylan J.

AU - Schuijers, Jurian

AU - Young, Richard A.

PY - 2019/12/5

Y1 - 2019/12/5

N2 - The gene expression programs that define the identity of each cell are controlled by master transcription factors (TFs) that bind cell-type-specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here, we present evidence that signaling factors for the WNT, TGF-β, and JAK/STAT pathways use their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator β-catenin interacts both with components of condensates and DNA-binding factors to selectively occupy super-enhancer-associated genes. We propose that the cell-type specificity of the response to signaling is mediated in part by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity.

AB - The gene expression programs that define the identity of each cell are controlled by master transcription factors (TFs) that bind cell-type-specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here, we present evidence that signaling factors for the WNT, TGF-β, and JAK/STAT pathways use their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator β-catenin interacts both with components of condensates and DNA-binding factors to selectively occupy super-enhancer-associated genes. We propose that the cell-type specificity of the response to signaling is mediated in part by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity.

KW - JAK/STAT

KW - TGF-β

KW - WNT

KW - gene regulation

KW - signaling pathway

KW - transcriptional condensates

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JO - Molecular cell

JF - Molecular cell

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ER -

Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes

Abstract

Keywords

ASJC Scopus subject areas

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