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Krug Brian, Hu Bo, Chen Haifen, Negrón-Lomas Claudia, Chen Xiao, El Mouatani Ahmed, Gretarsson Kristjan H, Ptack Adam, Deshmukh Shriya, Kabir Nisha, Jawhar Wajih, Andrade Augusto Faria, Jabbour Elias, Harutyunyan Ashot S, Wang Xinrui, Taylor Robert, Lee John J Y, Hulswit Maud, Faury Damien, Russo Caterina, Xu Xinjing, Yang Jiahan, Baguette Audrey, Dahl Nathan A, Weil Alexander G, Ellezam Benjamin, Dali Rola, Blanchette Mathieu, Wilson Khadija, Garcia Benjamin A, Soni Rajesh Kumar, Gallo Marco, Taylor Michael D, Kleinman Claudia L, Majewski Jacek, Jabado Nada, Lu Chao
Аннотация
Polycomb repressive complex 2 (PRC2)-mediated histone H3 K27 trimethylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, Polycomb-regulated genes can display long-range three-dimensional interactions, many of which resolve during lineage differentiation. Here we report that Polycomb-anchored looping is controlled by H3K27me3 spreading and regulates target gene silencing to influence cell fate specification. Using glioma-derived H3 Lys27-to-Met (H3K27M) mutations as tools to restrict H3K27me3 spreading, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened three-dimensional interactions that mirror the chromatin architecture of pluripotency. Conversely, H3K27me3 spread in pluripotent stem cells dilutes local cPRC1 chromatin concentration, weakening Polycomb loop contact frequencies. Disruption of cPRC1 binding or aggregation compromises stringent repression of Polycomb genes and induces differentiation and tumor regression of H3K27M-mutant glioma. These results identify the regulatory principles and disease implications of Polycomb looping and show that histone-modification-guided distribution of reader complexes is an important mechanism for nuclear compartment organization.