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<p>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.</p>

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H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs

  • 期刊论文

  • 发表日期：

    2026年5月18日

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  • Brian Krug,
  • Bo Hu,
  • Haifen Chen,
  • Claudia Negrón-Lomas,
  • Xiao Chen,
  • Ahmed El Mouatani,
  • Kristjan H. Gretarsson,
  • Adam Ptack,
  • Shriya Deshmukh,
  • Nisha Kabir,
  • Wajih Jawhar,
  • Augusto Faria Andrade,
  • Elias Jabbour,
  • Ashot S. Harutyunyan,
  • Xinrui Wang,
  • Robert Taylor,
  • John J. Y. Lee,
  • Maud Hulswit,
  • Damien Faury,
  • Caterina Russo,
  • Xinjing Xu,
  • Jiahan Yang,
  • Audrey Baguette,
  • Nathan A. Dahl,
  • Alexander G. Weil,
  • Benjamin Ellezam,
  • Rola Dali,
  • Mathieu Blanchette,
  • Khadija Wilson,
  • Benjamin A. Garcia,
  • Rajesh Kumar Soni,
  • Marco Gallo,
  • Michael D. Taylor,
  • Claudia L. Kleinman,
  • Jacek Majewski,
  • Nada Jabado,
  • Chao Lu

摘要

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.