JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications

Vignesh Kasinath; Curtis Beck; Paul Sauer; Simon Poepsel; Jennifer Kosmatka; Marco Faini; Daniel Toso; Ruedi Aebersold; Eva Nogales

doi:10.1126/science.abc3393

JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications

Science. 2021 Jan 22;371(6527):eabc3393. doi: 10.1126/science.abc3393.

Authors

Vignesh Kasinath¹, Curtis Beck², Paul Sauer^{3

4}, Simon Poepsel^{5

6}, Jennifer Kosmatka², Marco Faini⁷, Daniel Toso³, Ruedi Aebersold^{7

8}, Eva Nogales^{1

2

4

9}

Affiliations

¹ QB3 Institute, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA. enogales@lbl.gov vigneshk@berkeley.edu.
² Department of Molecular and Cellular Biology, University of California, Berkeley, CA, USA.
³ QB3 Institute, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
⁴ Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
⁵ University of Cologne, Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, Cologne, Germany.
⁶ Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁷ Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
⁸ Faculty of Science, University of Zürich, Zürich, Switzerland.
⁹ Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.

Abstract

Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) cooperate to determine cell identity by epigenetic gene expression regulation. However, the mechanism of PRC2 recruitment by means of recognition of PRC1-mediated H2AK119ub1 remains poorly understood. Our PRC2 cryo-electron microscopy structure with cofactors JARID2 and AEBP2 bound to a H2AK119ub1-containing nucleosome reveals a bridge helix in EZH2 that connects the SET domain, H3 tail, and nucleosomal DNA. JARID2 and AEBP2 each interact with one ubiquitin and the H2A-H2B surface. JARID2 stimulates PRC2 through interactions with both the polycomb protein EED and the H2AK119-ubiquitin, whereas AEBP2 has an additional scaffolding role. The presence of these cofactors partially overcomes the inhibitory effect that H3K4me3 and H3K36me3 exert on core PRC2 (in the absence of cofactors). Our results support a key role for JARID2 and AEBP2 in the cross-talk between histone modifications and PRC2 activity.

Publication types

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

MeSH terms

Animals
Cryoelectron Microscopy
Gene Expression Regulation
Histone Code*
Histones / metabolism
Humans
Nucleosomes / metabolism
PR-SET Domains
Polycomb Repressive Complex 2 / chemistry
Polycomb Repressive Complex 2 / metabolism*
Repressor Proteins / metabolism*
Ubiquitin / metabolism
Xenopus

Substances

AEBP2 protein, human
Histones
JARID2 protein, human
Nucleosomes
Repressor Proteins
Ubiquitin
histone H3 trimethyl Lys4
Polycomb Repressive Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding