A partially disordered region connects gene repression and activation functions of EZH2

Jiao, Lianying; Shubbar, Murtada; Yang, Xin; Zhang, Qi; Chen, Siming; Wu, Qiong; Chen, Zhe; Rizo, Josep; Liu, Xin

doi:10.1073/pnas.1914866117

A partially disordered region connects gene repression and activation functions of EZH2

Journal Article · Mon Jul 06 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1914866117· OSTI ID:1642238

^[1]; Shubbar, Murtada ^[1]; ^[1]; ^[1]; Chen, Siming ^[1]; Wu, Qiong ^[1]; Chen, Zhe ^[1]; Rizo, Josep ^[1]; Liu, Xin ^[1]

Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)

Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which minimally requires two other subunits, EED and SUZ12, for enzymatic activity. EZH2 has been traditionally known to mediate histone H3K27 trimethylation, a hallmark of silent chromatin. Emerging evidence indicates that EZH2 also activates gene expression in cancer cells in a context distinct from canonical PRC2. The molecular mechanism underlying the functional conversion of EZH2 from a gene repressor to an activator is unclear. In this work, we show that EZH2 harbors a hidden, partially disordered transactivation domain (TAD) capable of interacting with components of active transcription machinery, mimicking archetypal acidic activators. The EZH2 TAD comprises the SRM (Stimulation-Responsive Motif) and SANT1 (SWI3, ADA2, N-CoR, and TFIIIB 1) regions that are normally involved in H3K27 methylation. The crystal structure of an EZH2–EED binary complex indicates that the EZH2 TAD mediates protein oligomerization in a noncanonical PRC2 context and is entirely sequestered. The EZH2 TAD can be unlocked by cancer-specific EZH2 phosphorylation events to undergo structural transitions that may enable subsequent transcriptional coactivator binding. The EZH2 TAD directly interacts with the transcriptional coactivator and histone acetyltransferase p300 and activates gene expression in a p300-dependent manner in cells. The corresponding TAD may also account for the gene activation function of EZH1, the paralog of EZH2. Distinct kinase signaling pathways that are known to abnormally convert EZH2 into a gene activator in cancer cells can now be understood in a common structural context of the EZH2 TAD.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS); SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: American Heart Association (AHA); Cancer Prevention and Research Institute of Texas (CPRIT); Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research; National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Rita Allen Foundation; USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); UT Southwestern Medical Center Endowed Scholar; Welch Foundation

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357; AC02-76SF00515

OSTI ID:: 1642238

Alternate ID(s):: OSTI ID: 1783873

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 29 Vol. 117; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
EZH2
gene activation
p300
phosphorylation
transcriptional activation domain

A partially disordered region connects gene repression and activation functions of EZH2

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