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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Nature genetics
2026
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/42151415/ |
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Table of Contents:
- H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs. 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 Histones Chromatin Animals Humans Cell Differentiation Polycomb Repressive Complex 1 Glioma Polycomb Repressive Complex 2 Pluripotent Stem Cells Mutation Methylation Polycomb-Group Proteins Mice Heterochromatin Cell Cycle Proteins 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.