The Methylome of Vertebrate Sex Chromosomes

Abstract

DNA methylation is a key epigenetic modification in vertebrate genomes known to be involved in the regulation of gene expression, X chromosome inactivation, genomic imprinting, chromatin structure, and control of transposable elements. DNA methylation is common to all eukaryote genomes, but we still lack a complete understanding of the variation in DNA methylation patterns on sex chromosomes and between the sexes in diverse species. To better understand sex chromosome DNA methylation patterns between different amniote vertebrates, we review literature that has analyzed the genome-wide distribution of DNA methylation in mammals and birds. In each system, we focus on DNA methylation patterns on the autosomes versus the sex chromosomes.

Keywords: 5mC; DNA methylation; X chromosome inactivation; bird; dosage compensation; mammal; sex chromosome.

Figure 1

Phylogenetic relationships and DNA methylation profiles of amniote vertebrates. (a) Sex chromosome homologies with the therian mammal X conserved region (green) and the eutherian X added region (orange), which is autosomal in marsupials. The platypus X chromosomes and the chicken Z chromosome (purple) share extensive homology, especially X5 which is almost entirely homologous to the chicken Z. However, despite this homology, these sex chromosome systems have independently evolved. (b) Metagene analysis (adapted from [9]) of DNA methylation levels across transcription start sites (TSSs) of expressed autosomal genes in males (blue) and females (red). The absolute level of DNA methylation varies between species, but there is a conserved pattern of low DNA methylation flanked by high methylation (especially downstream of TSSs in marsupials, monotremes, and birds). (c) Metagene analysis (adapted from [9]) of DNA methylation levels across TSSs of all genes annotated on the chicken Z and platypus Xs, and genes subject to X chromosome inactivation (XCI) in marsupials and eutherians, in males (blue) and females (red). In chicken and platypus, the methylation patterns do not vary between sexes. However, in female marsupials, DNA methylation flanking TSSs is reduced relative to males, whereas, in female eutherians, DNA methylation at TSSs is increased relative to males. (d) Density of CpG dinucleotides relative to annotated TSSs on autosomes (black) and the X/Z chromosome (grey). In all species, CpG densities peak at TSSs, with X chromosomes mirroring the autosomes in therian mammals. The change in X chromosome versus autosome density in platypus likely results from the relatively few genes anchored to the Xs. The chicken Z chromosome has a reduced density of CpGs at TSSs compared to the autosomes, which could result from a diminished function for DNA methylation in Z chromosome gene regulation (see text).

Figure 2

Typical CpG island structure in the promoter (blue) and into the gene body (red) of a eutherian gene. DNA methylation levels are shown for expressed genes, along with how methylation levels correlate with gene expression [53,54,55]. CpG islands (CGIs) are regions of dense CpGs, within a window of at least 500 bp, that generally exhibit low methylation in expressed genes [59,60]. CpG shores and shelves contain fewer CpG sites. Shores have more dynamic DNA methylation levels depending on tissue type [53,59,60]. There is high DNA methylation in seas, which is thought to silence transposable elements [61]. The DNA methylation level (from Figure 1b) across TSSs of expressed genes in mouse liver is shown below the gene. Dashes immediately above CGIs, shores, and shelves represent CpG dinucleotides, with highest density in the CGI near the TSS. Statements about the upstream shore and shelf apply also to gene body shore and shelf.