High-resolution analysis of epigenetic changes associated with X inactivation

Area of Science:

• Epigenetics
• Genomics
• Developmental Biology

Background:

• X-chromosome inactivation (XCI) silences one X chromosome in female cells, involving heterochromatic changes like H3K27me3 acquisition.
• Mechanisms establishing heterochromatin during XCI remain incompletely understood.

Purpose of the Study:

• To investigate dynamic epigenetic landscape changes within the X-inactivation center (Xic) during differentiation.
• To elucidate the role and dynamics of H3K27me3 deposition during XCI in female murine ES cells.

Main Methods:

• Chromatin immunoprecipitation followed by sequencing (ChIP-seq) and chip-chip analysis.
• RNA expression analysis.
• Allele-specific SNP mapping on polymorphic X chromosomes.

Main Results:

• Dynamic epigenetic changes observed at the Xic, with Tsix repression and H3K27me3 deposition in both sexes.
• Female-specific active epigenetic landscape at the Xist locus, correlating with high Xist expression.
• Genome-wide, female-specific increase of H3K27me3 on the inactive X (Xi), associated with gene silencing and decreased H3K4me3.

Conclusions:

• H3K27me3 deposition is a key mechanism for gene silencing across the Xi during XCI.
• Dynamic epigenetic regulation at the Xic controls Xist expression and subsequent XCI initiation.
• The study defines novel loci with enriched H3K27me3 and clarifies the chromosome-wide association of H3K27me3 with the Xi.