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Histone H2Bub1 deubiquitylation is essential for mouse development, but does not regulate global RNA polymerase II transcription

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journal contribution
posted on 27.09.2021, 23:48 by F Wang, Farrah El-SaafinFarrah El-Saafin, T Ye, M Stierle, L Negroni, M Durik, V Fischer, D Devys, SD Vincent, L Tora
Co-activator complexes dynamically deposit post-translational modifications (PTMs) on histones, or remove them, to regulate chromatin accessibility and/or to create/erase docking surfaces for proteins that recognize histone PTMs. SAGA (Spt-Ada-Gcn5 Acetyltransferase) is an evolutionary conserved multisubunit co-activator complex with modular organization. The deubiquitylation module (DUB) of mammalian SAGA complex is composed of the ubiquitin-specific protease 22 (USP22) and three adaptor proteins, ATXN7, ATXN7L3 and ENY2, which are all needed for the full activity of the USP22 enzyme to remove monoubiquitin (ub1) from histone H2B. Two additional USP22-related ubiquitin hydrolases (called USP27X or USP51) have been described to form alternative DUBs with ATXN7L3 and ENY2, which can also deubiquitylate H2Bub1. Here we report that USP22 and ATXN7L3 are essential for normal embryonic development of mice, however their requirements are not identical during this process, as Atxn7l3−/− embryos show developmental delay already at embryonic day (E) 7.5, while Usp22−/− embryos are normal at this stage, but die at E14.5. Global histone H2Bub1 levels were only slightly affected in Usp22 null embryos, in contrast H2Bub1 levels were strongly increased in Atxn7l3 null embryos and derived cell lines. Our transcriptomic analyses carried out from wild type and Atxn7l3−/− mouse embryonic stem cells (mESCs), or primary mouse embryonic fibroblasts (MEFs) suggest that the ATXN7L3-related DUB activity regulates only a subset of genes in both cell types. However, the gene sets and the extent of their deregulation were different in mESCs and MEFs. Interestingly, the strong increase of H2Bub1 levels observed in the Atxn7l3−/− mESCs, or Atxn7l3−/− MEFs, does not correlate with the modest changes in RNA Polymerase II (Pol II) occupancy and lack of changes in Pol II elongation observed in the two Atxn7l3−/− cellular systems. These observations together indicate that deubiquitylation of histone H2Bub1 does not directly regulate global Pol II transcription elongation.

Funding

This study was supported by grants from European Research Council (ERC) (ERC-2013-Advanced grant 340551, Birtoaction), Agence Nationale de la Recherche (ANR) PICen-19-CE11-0003-02 and EpiCAST-19-CE12-0029-01 grants, NIH 1R01GM131626-01 grant (to LT), and ANR-18-CE12-0026 grant (to DD), by IGBMC International PhD program LABEX fellowship (to FW); and by the IdEx-University of Strasbourg PhD program and by the "Fondation pour la Recherche Medicale" (FRM) association (FDT201904008368) (to VF), and an ANR-10-LABX-0030-INRT grant, under the frame program Investissements d'Avenir ANR-10-IDEX-0002-02.

History

Publication Date

01/08/2021

Journal

Cell Death and Differentiation

Volume

28

Issue

8

Pagination

19p. (p. 2385-2403)

Publisher

Springer

ISSN

1350-9047

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The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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