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

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

doi:10.1016/j.cell.2018.10.042

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

Cell. 2018 Dec 13;175(7):1842-1855.e16. doi: 10.1016/j.cell.2018.10.042. Epub 2018 Nov 15.

Authors

Ann Boija¹, Isaac A Klein², Benjamin R Sabari¹, Alessandra Dall'Agnese¹, Eliot L Coffey³, Alicia V Zamudio³, Charles H Li³, Krishna Shrinivas⁴, John C Manteiga³, Nancy M Hannett¹, Brian J Abraham¹, Lena K Afeyan³, Yang E Guo¹, Jenna K Rimel⁵, Charli B Fant⁵, Jurian Schuijers¹, Tong Ihn Lee¹, Dylan J Taatjes⁵, Richard A Young⁶

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
³ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA.
⁶ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: young@wi.mit.edu.

Abstract

Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well characterized, but little is known about the mechanisms by which ADs effect gene activation. Here, we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation.

Keywords: activation domain; gene activation; mediator; phase separation; transcription; transcription factor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
HEK293 Cells
Humans
Mice
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / metabolism*
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism*
Protein Domains
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism*
Transcriptional Activation / physiology*

Substances

Octamer Transcription Factor-3
Pou5f1 protein, mouse
Receptors, Estrogen

Abstract

Publication types

MeSH terms

Substances

Grants and funding