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- The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development.
The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development.
Citation | “The Deubiquitinase Usp9X Regulates Prc2-Mediated Chromatin Reprogramming During Mouse Development.”. Nature Communications, p. 1865. . |
Author | Trisha A Macrae, Miguel Ramalho-Santos |
Abstract |
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. |
Year of Publication |
2021
|
Journal |
Nature communications
|
Volume |
12
|
Issue |
1
|
Number of Pages |
1865
|
Date Published |
12/2021
|
ISSN Number |
2041-1723
|
DOI |
10.1038/s41467-021-21910-0
|
Alternate Journal |
Nat Commun
|
PMID |
33767158
|
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