Competition between PRC2.1 and 2.2 subcomplexes regulates PRC2 chromatin occupancy in human stem cells

Daniel T Youmans; Anne R Gooding; Robin D Dowell; Thomas R Cech

doi:10.1016/j.molcel.2020.11.044

Competition between PRC2.1 and 2.2 subcomplexes regulates PRC2 chromatin occupancy in human stem cells

Mol Cell. 2021 Feb 4;81(3):488-501.e9. doi: 10.1016/j.molcel.2020.11.044. Epub 2020 Dec 17.

Authors

Daniel T Youmans¹, Anne R Gooding², Robin D Dowell³, Thomas R Cech⁴

Affiliations

¹ BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA; Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA; Medical Scientist Training Program, University of Colorado School of Medicine, Aurora, CO 80045, USA; Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
² Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
³ BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA; Department of Molecular Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80303, USA.
⁴ BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA; Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA; Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80303, USA. Electronic address: thomas.cech@colorado.edu.

Abstract

Polycomb repressive complex 2 (PRC2) silences expression of developmental transcription factors in pluripotent stem cells by methylating lysine 27 on histone H3. Two mutually exclusive subcomplexes, PRC2.1 and PRC2.2, are defined by the set of accessory proteins bound to the core PRC2 subunits. Here we introduce separation-of-function mutations into the SUZ12 subunit of PRC2 to drive it into a PRC2.1 or 2.2 subcomplex in human induced pluripotent stem cells (iPSCs). We find that PRC2.2 occupies polycomb target genes at low levels and that homeobox transcription factors are upregulated when this complex is exclusively present. In contrast with previous studies, we find that chromatin occupancy of PRC2 increases drastically when it is forced to form PRC2.1. Additionally, several cancer-associated mutations also coerce formation of PRC2.1. We suggest that PRC2 chromatin occupancy can be altered in the context of disease or development by tuning the ratio of PRC2.1 to PRC2.2.

Keywords: CRISPR; EZH2; H3K27me3; PRC2; SUZ12; cancer; epigenetics; homeobox; polycomb; stem cells.

Publication types

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

MeSH terms

Binding Sites
Binding, Competitive
Chromatin / genetics
Chromatin / metabolism*
Gene Expression Regulation
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Induced Pluripotent Stem Cells / metabolism*
Mutation
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Polycomb Repressive Complex 2 / genetics
Polycomb Repressive Complex 2 / metabolism*
Protein Binding
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Chromatin
Homeodomain Proteins
Neoplasm Proteins
SUZ12 protein, human
Transcription Factors
Polycomb Repressive Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding