In mammals, dosage compensation for the sex chromosomes is achieved by transcriptional silencing of one of the two X chromosomes in females. The inactive X adopts a particular epigenetic state, characterised by specific histones, histone marks, DNA methylation and 3D chromatin structure. As allelic resolution with short-read sequencing is limited, we do not yet have chromosome-wide phased methylomes of the active and inactive X.
We define complete X methylomes in mouse placenta and neural stem cells (NSCs) via long-read nanopore sequencing, revealing starkly different modes of X chromosome silencing. In both tissues we observe global hypomethylation of the inactive X with regards to autosomes or the active X, but only in NSCs are the CpG islands hypermethylated, pointing to a different mode of epigenetic silencing in placenta. Transcriptional start sites in the placenta were also not hypermethylated. Quantitative analysis of methylation properties showed that methylation in the placenta is less symmetrical and more disordered than in NSCs, as is the methylation on the NSC inactive X compared to the NSC active X or autosomes. We also include a cross-tissue overview of inactive X base modifications patterns, including hydroxmethylation and non-CG methylation, derived from shallow nanopore sequencing.
Complete, phased methylomes of the X and cross-tissue surveys highlight the different modes of X inactivation.