Abstract
SummaryDuring 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.
Highlights
Successful development requires the establishment and maintenance of euchromatin and heterochromatin in different parts of the genome
The reads were split according to content of allele-specific SNPs (B6, mapping to Xi; Cast, mapping to active X); this allelic information was analyzed in detail to define X chromosome inactivation (XCI)-specific changes
We found that gene promoters that are rapidly H3K27-deacetylated preferentially reside in gene poor, LINE-dense regions in proximity to lamina-associated domains (LADs) and the Xist locus (Figure 2D)
Summary
Successful development requires the establishment and maintenance of euchromatin and heterochromatin in different parts of the genome. Stable silencing of some genic regions occurs as epigenetic memory continues to accrue, leading to facultative heterochromatin formation (Trojer and Reinberg, 2007). Multiple layers of chromatin modifications are believed to enable stable transcriptional silencing. Little is known about how facultative heterochromatin is dynamically formed and to what extent chromatin changes are involved in the establishment of gene silencing. A powerful model for developmentally induced gene silencing and formation of facultative heterochromatin is X chromosome inactivation (XCI) in female mammals. The role for chromatin changes in maintenance of the inactive state has been extensively studied (Disteche and Berletch, 2015), almost nothing is known about their role in the initiation of gene silencing
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