The Implication of Early Chromatin Changes in X Chromosome Inactivation
Research output: Contribution to journal › Journal article › Research › peer-review
During development, the precise relationships between transcription and chromatin modifications often remain unclear. We use the X chromosome inactivation (XCI) paradigm to explore the implication of chromatin changes in gene silencing. Using female mouse embryonic stem cells, we initiate XCI by inducing Xist and then monitor the temporal changes in transcription and chromatin by allele-specific profiling. This reveals histone deacetylation and H2AK119 ubiquitination as the earliest chromatin alterations during XCI. We show that HDAC3 is pre-bound on the X chromosome and that, upon Xist coating, its activity is required for efficient gene silencing. We also reveal that first PRC1-associated H2AK119Ub and then PRC2-associated H3K27me3 accumulate initially at large intergenic domains that can then spread into genes only in the context of histone deacetylation and gene silencing. Our results reveal the hierarchy of chromatin events during the initiation of XCI and identify key roles for chromatin in the early steps of transcriptional silencing.
| Original language | English |
|---|---|
| Journal | Cell |
| Volume | 176 |
| Issue number | 1-2 |
| Pages (from-to) | 182-197.e23 |
| ISSN | 0092-8674 |
| DOIs | |
| Publication status | Published - 10 Jan 2019 |
| Externally published | Yes |
Bibliographical note
Funding Information:
We are grateful to Magdalena Zernicka-Goetz and Elizabeth Blackburn for their continuing support of this project. We are thankful to Samuel Collombet, Tomasz Chelmicki, Pierre Gestraud, Aurelie Teissandier, Nicolas Servant, and Emmanuel Barillot for help with the project and members of the Heard lab for helpful discussions. We are grateful to Anton Wutz for sharing his TXY ESC line. We also thank the tissue-imaging platform—PICT-IBiSA (UMR3215/U934) and the next-generation sequencing platform of Institut Curie. This work was funded by ERC advanced investigator awards (ERC-ADG-2014 671027 to E.H. and ERC-ADG-2015 693023 to P.C.), Labellisation La Ligue, ANR (DoseX 2017: ANR-17-CE12-0029, Labex DEEP: ANR-11- LBX-0044, ABS4NGS: ANR-11-BINF-0001, and part of the IDEX PSL: ANR-10-IDEX-0001-02 PSL to E.H.), a Sir Henry Wellcome Postdoctoral Fellowship (201369/Z/16/Z; to J.J.Z.), Volkswagen Foundation funding (to P.C.), and “Région Ile-de-France” and Fondation pour la Recherche Médicale grants (to D.L.).
Funding Information:
We are grateful to Magdalena Zernicka-Goetz and Elizabeth Blackburn for their continuing support of this project. We are thankful to Samuel Collombet, Tomasz Chelmicki, Pierre Gestraud, Aurelie Teissandier, Nicolas Servant, and Emmanuel Barillot for help with the project and members of the Heard lab for helpful discussions. We are grateful to Anton Wutz for sharing his TXY ESC line. We also thank the tissue-imaging platform—PICT-IBiSA (UMR3215/U934) and the next-generation sequencing platform of Institut Curie. This work was funded by ERC advanced investigator awards ( ERC-ADG-2014 671027 to E.H. and ERC-ADG-2015 693023 to P.C.), Labellisation La Ligue , ANR ( DoseX 2017 : ANR-17-CE12-0029 , Labex DEEP : ANR-11- LBX-0044 , ABS4NGS : ANR-11-BINF-0001 , and part of the IDEX PSL : ANR-10-IDEX-0001-02 PSL to E.H.), a Sir Henry Wellcome Postdoctoral Fellowship ( 201369/Z/16/Z ; to J.J.Z.), Volkswagen Foundation funding (to P.C.), and “Région Ile-de-France” and Fondation pour la Recherche Médicale grants (to D.L.).
Publisher Copyright:
© 2018 The Author(s)
- embryonic stem cells, epigenetics, histone acetylation, histone deacetylase, Polycomb, PRC1, PRC2, X chromosome inactivation, Xist
Research areas
ID: 391637764