Cell
Volume 176, Issues 1–2, 10 January 2019, Pages 182-197.e23
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Article
The Implication of Early Chromatin Changes in X Chromosome Inactivation

https://doi.org/10.1016/j.cell.2018.11.041Get rights and content
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Highlights

  • An epigenomic roadmap for initiation of X chromosome inactivation (XCI)

  • Histone deacetylation and H2A ubiquitination are among the earliest XCI events

  • HDAC3-mediated histone deacetylation is required for efficient XCI

  • PcG marks are first deposited intergenically and spread when gene silencing occurs

Summary

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.

Keywords

epigenetics
X chromosome inactivation
embryonic stem cells
Xist
histone deacetylase
histone acetylation
Polycomb
PRC1
PRC2

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These authors contributed equally

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