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The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development
Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of development...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994559/ https://www.ncbi.nlm.nih.gov/pubmed/33767158 http://dx.doi.org/10.1038/s41467-021-21910-0 |
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author | Macrae, Trisha A. Ramalho-Santos, Miguel |
author_facet | Macrae, Trisha A. Ramalho-Santos, Miguel |
author_sort | Macrae, Trisha A. |
collection | PubMed |
description | Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of this global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of “stemness” and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states. |
format | Online Article Text |
id | pubmed-7994559 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-79945592021-04-16 The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development Macrae, Trisha A. Ramalho-Santos, Miguel Nat Commun Article Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of this global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of “stemness” and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states. Nature Publishing Group UK 2021-03-25 /pmc/articles/PMC7994559/ /pubmed/33767158 http://dx.doi.org/10.1038/s41467-021-21910-0 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Macrae, Trisha A. Ramalho-Santos, Miguel The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development |
title | The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development |
title_full | The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development |
title_fullStr | The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development |
title_full_unstemmed | The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development |
title_short | The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development |
title_sort | deubiquitinase usp9x regulates prc2-mediated chromatin reprogramming during mouse development |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994559/ https://www.ncbi.nlm.nih.gov/pubmed/33767158 http://dx.doi.org/10.1038/s41467-021-21910-0 |
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