The role of m6A RNA methylation in the maintenance of X chromosome inactivation and X-to-autosome dosage compensation in early embryonic lineages

In mammals, while X chromosome inactivation (XCI) balances the dosage of X-linked gene expression between sexes, upregulation of active-X balances the dosage of monoallelic X-linked genes with biallelic autosomal genes (AA). Here, we have investigated the role of m6A RNA methylation in the maintenance of XCI and X-to-autosome (X-to-A) dosage compensation in early embryonic lineages: epiblast stem cells (EpiSCs), trophoblast stem cells (TSCs), and extraembryonic endoderm stem cells (XENs). We find that the depletion of m6A RNA methylation in these cells does not affect the maintenance of inactive-X silencing. Moreover, we show that m6A marks are less enriched on X-linked transcripts than the autosomal transcripts in early embryonic lineages. Notably, we demonstrate that the extent of X-to-A dosage compensation varies with m6A methylation level. Finally, we show that the depletion of m6A partly disrupts X-to-A dosage compensation in a cell-type-specific manner. Together, our study provides significant insight into the role of m6A RNA methylation in dosage compensation.