Abstract
X chromosome inactivation (XCI) mediated by differential DNA methylation between sexes is an iconic example of epigenetic regulation. Although XCI is shared between eutherians and marsupials, the role of DNA methylation in marsupial XCI remains contested. Here, we examine genome-wide signatures of DNA methylation across fives tissues from a male and female koala (Phascolarctos cinereus), and present the first whole-genome, multi-tissue marsupial ‘methylome atlas’. Using these novel data, we elucidate divergent versus common features of representative marsupial and eutherian DNA methylation. First, tissue-specific differential DNA methylation in koalas primarily occurs in gene bodies. Second, females show significant global reduction (hypomethylation) of X chromosome DNA methylation compared to males. We show that this pattern is also observed in eutherians. Third, on average, promoter DNA methylation shows little difference between male and female koala X chromosomes, a pattern distinct from that of eutherians. Fourth, the sex-specific DNA methylation landscape upstream of Rsx, the primary lncRNA associated with marsupial XCI, is consistent with the epigenetic regulation of female-specific (and presumably inactive X chromosome-specific) expression. Finally, we use the prominent female X chromosome hypomethylation and classify 98 previously unplaced scaffolds as X-linked, contributing an additional 14.6 Mb (21.5%) to genomic data annotated as the koala X chromosome. Our work demonstrates evolutionarily divergent pathways leading to functionally conserved patterns of XCI in two deep branches of mammals.
Highlights
X chromosome inactivation (XCI) is a classic example of sex chromosome regulation in which one of the two X chromosomes in females is silenced as a mechanism thought to adjust the expression levels of X-linked genes [1]
Whole-genome bisulfite sequencing is a gold-standard of genomic DNA methylation analysis, as it produces information on most cytosines in a genome
The novel multi-tissue, nucleotide-resolution DNA methylation maps of koalas reveal genome-wide patterns of tissue-specific differential DNA methylation enriched in gene bodies
Summary
X chromosome inactivation (XCI) is a classic example of sex chromosome regulation in which one of the two X chromosomes in females is silenced as a mechanism thought to adjust the expression levels of X-linked genes [1]. Out of five repressive marks examined in two marsupial studies, H3K9me, H4K20me and HP1α were enriched [14], while H3K27me and H3K9me2 [15] were not enriched, on the inactive X chromosome These differences suggest that evolutionary pathways leading to XCI probably differ between eutherians and marsupials, and that novel insights into the mechanism of XCI can be gained from comparative studies. Waters et al [19] analysed reduced representation bisulfite sequencing (RRBS) data of a male and female opossum (Monodelphis domestica) and proposed that female X chromosomes in marsupials, but not in eutherians, exhibit hypomethylation near the transcription start sites (TSSs). All these studies analysed different marsupial species and tissues. Our data provide the first multi-tissue, whole-genome methylome resource of any marsupial enabling us to show distinctive impacts of DNA methylation on tissue-specific gene expression in marsupials, as well as on XCI in eutherians and marsupials
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