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

• Published in: Molecular cell 2021-02, Vol.81 (3), p.488-501.e9
• Main Authors: Youmans, Daniel T., Gooding, Anne R., Dowell, Robin D., Cech, Thomas R.
• Format: Article
• Language: English
• Subjects: Binding Sites; Binding, Competitive; cancer; Chromatin - genetics; Chromatin - metabolism; CRISPR; epigenetics; EZH2; Gene Expression Regulation; H3K27me3; homeobox; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Induced Pluripotent Stem Cells - metabolism; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; polycomb; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; PRC2; Protein Binding; stem cells; SUZ12; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.11.044

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. [Display omitted] •Mutations in the SUZ12 subunit of PRC2 coerce formation of PRC2.1 or 2.2•PRC2.1 and 2.2 display high and low affinity for PRC2 target genes, respectively•Human stem cells expressing solely PRC2.1 gain H3K27me3 at polycomb target sites•Cancer mutations in SUZ12 force PRC2.1 formation and increase chromatin occupancy Polycomb repressive complex 2 (PRC2) is comprised of two distinct subcomplexes, PRC2.1 and PRC2.2. Youmans et al. identify separation-of-function and cancer-associated mutations in PRC2 that coerce formation of PRC2.1 or PRC2.2. They show that the subcomplexes bind overlapping target genes in human stem cells but with disparate affinity.