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Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation
Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction. This process is essential for embryonic stem cell (ESC) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295753/ https://www.ncbi.nlm.nih.gov/pubmed/35617427 http://dx.doi.org/10.1073/pnas.2201883119 |
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author | Kraft, Katerina Yost, Kathryn E. Murphy, Sedona E. Magg, Andreas Long, Yicheng Corces, M. Ryan Granja, Jeffrey M. Wittler, Lars Mundlos, Stefan Cech, Thomas R. Boettiger, Alistair N. Chang, Howard Y. |
author_facet | Kraft, Katerina Yost, Kathryn E. Murphy, Sedona E. Magg, Andreas Long, Yicheng Corces, M. Ryan Granja, Jeffrey M. Wittler, Lars Mundlos, Stefan Cech, Thomas R. Boettiger, Alistair N. Chang, Howard Y. |
author_sort | Kraft, Katerina |
collection | PubMed |
description | Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction. This process is essential for embryonic stem cell (ESC) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spreading of H3K27me3 on the linear genome. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remain unclear. Here, we apply H3K27me3 HiChIP, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes. Genetic deletion of H3K27me3 loop anchors results in disruption of spatial contact between distant loci and altered H3K27me3 in cis, both locally and megabases away on the same chromosome. In mouse embryos, loop anchor deletion leads to ectopic activation of the partner gene, suggesting that Polycomb-associated loops control gene silencing during development. Further, we find that alterations in PRC2 occupancy resulting from an RNA binding–deficient EZH2 mutant are accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 uses RNA binding to enhance long-range chromosome folding and H3K27me3 spreading. Developmental gene loci have unique roles in Polycomb spreading, emerging as important architectural elements of the epigenome. |
format | Online Article Text |
id | pubmed-9295753 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-92957532022-07-20 Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation Kraft, Katerina Yost, Kathryn E. Murphy, Sedona E. Magg, Andreas Long, Yicheng Corces, M. Ryan Granja, Jeffrey M. Wittler, Lars Mundlos, Stefan Cech, Thomas R. Boettiger, Alistair N. Chang, Howard Y. Proc Natl Acad Sci U S A Biological Sciences Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction. This process is essential for embryonic stem cell (ESC) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spreading of H3K27me3 on the linear genome. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remain unclear. Here, we apply H3K27me3 HiChIP, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes. Genetic deletion of H3K27me3 loop anchors results in disruption of spatial contact between distant loci and altered H3K27me3 in cis, both locally and megabases away on the same chromosome. In mouse embryos, loop anchor deletion leads to ectopic activation of the partner gene, suggesting that Polycomb-associated loops control gene silencing during development. Further, we find that alterations in PRC2 occupancy resulting from an RNA binding–deficient EZH2 mutant are accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 uses RNA binding to enhance long-range chromosome folding and H3K27me3 spreading. Developmental gene loci have unique roles in Polycomb spreading, emerging as important architectural elements of the epigenome. National Academy of Sciences 2022-05-26 2022-05-31 /pmc/articles/PMC9295753/ /pubmed/35617427 http://dx.doi.org/10.1073/pnas.2201883119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Kraft, Katerina Yost, Kathryn E. Murphy, Sedona E. Magg, Andreas Long, Yicheng Corces, M. Ryan Granja, Jeffrey M. Wittler, Lars Mundlos, Stefan Cech, Thomas R. Boettiger, Alistair N. Chang, Howard Y. Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation |
title | Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation |
title_full | Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation |
title_fullStr | Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation |
title_full_unstemmed | Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation |
title_short | Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation |
title_sort | polycomb-mediated genome architecture enables long-range spreading of h3k27 methylation |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295753/ https://www.ncbi.nlm.nih.gov/pubmed/35617427 http://dx.doi.org/10.1073/pnas.2201883119 |
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