The Implication of Early Chromatin Changes in X Chromosome Inactivation

Jan Jakub Żylicz (1, 2, 3, 4) , Aurélie Bousard (1, 2, 3) , Kristina Žumer (5) , Francois Dossin (1, 2, 3) , Eusra Mohammad (5) , Simão Teixeira da Rocha (6) , Björn Schwalb (5) , Laurène Syx (1, 2, 3) , Florent Dingli (1, 7) , Damarys Loew (1, 7) , Patrick Cramer (5) , Edith Heard (1, 2, 3)

1 PSL - Université Paris Sciences et Lettres
2 Génétique et Biologie du Développement
3 SU FM - Sorbonne Université - Faculté de Médecine
4 CAM - University of Cambridge [UK]
5 Max-Planck-Institut für Biophysikalische Chemie - Max Planck Institute for Biophysical Chemistry [Göttingen]
6 ULISBOA - Universidade de Lisboa = University of Lisbon
7 Institut Curie [Paris]

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.

Mots clés: epigenetics; X chromosome inactivation; embryonic stem cells; Xist; histone deacetylase; histone acetylation; Polycomb; PRC1; PRC2

Domaines: Biologie du développement; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Jan Jakub Żylicz, Aurélie Bousard, Kristina Žumer, Francois Dossin, Eusra Mohammad, et al.. The Implication of Early Chromatin Changes in X Chromosome Inactivation. Cell, 2019, 176 (1-2), pp.182-197.e23. ⟨10.1016/j.cell.2018.11.041⟩. ⟨hal-01997790⟩