Gene Body-Specific Methylation on the Active X Chromosome

TLDR

Differential DNA methylation regulates gene expression, yet the overall methylation pattern of the active and inactive X chromosomes, beyond promoter CpG islands on Xi, remains unknown. The authors performed allele‑specific analysis of over 1,000 informative loci across the human X chromosome to map methylation patterns. The active X chromosome exhibits more than twice the allele‑specific methylation of the inactive X, concentrated in gene bodies; before X inactivation these sites are biallelically methylated, producing a bipartite program of promoter hypomethylation and gene‑body hypermethylation that links global methylation to expression potential.

Abstract

Differential DNA methylation is important for the epigenetic regulation of gene expression. Allele-specific methylation of the inactive X chromosome has been demonstrated at promoter CpG islands, but the overall pattern of methylation on the active X(Xa) and inactive X (Xi) chromosomes is unknown. We performed allele-specific analysis of more than 1000 informative loci along the human X chromosome. The Xa displays more than two times as much allele-specific methylation as Xi. This methylation is concentrated at gene bodies, affecting multiple neighboring CpGs. Before X inactivation, all of these Xa gene body–methylated sites are biallelically methylated. Thus, a bipartite methylation-demethylation program results in Xa-specific hypomethylation at gene promoters and hypermethylation at gene bodies. These results suggest a relationship between global methylation and expression potentiality.