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Several lines of evidence suggest that the presence of the Y chromosome influences DNA methylation of autosomal loci. To better understand the impact of the Y chromosome on autosomal DNA methylation patterns and its contribution to sex bias in methylation, we identified Y chromosome dependent differentially methylated regions (yDMRs) using whole-genome bisulfite sequencing methylation data from livers of mice with different combinations of sex-chromosome complement and gonadal sex. Nearly 90% of the autosomal yDMRs mapped to transposable elements (TEs) and most of them had lower methylation in XY compared to XX or XO mice. Follow-up analyses of four reporter autosomal yDMRs showed that Y-dependent methylation levels were consistent across most somatic tissues but varied in strains with different origins of the Y chromosome, suggesting that genetic variation in the Y chromosome influenced methylation levels of autosomal regions. Mice lacking the q-arm of the Y chromosome (B6.NPYq-2) as well as mice with a loss-of-function mutation in Kdm5d showed no differences in methylation levels compared to wild type mice. In conclusion, the Y-linked modifier of TE methylation is likely to reside on the short arm of Y chromosome and further studies are required to identify this gene. [ABSTRACT FROM AUTHOR]

Graph: Figure 5 BCL6, AR, and ESR1 influence DNA methylation at sDMRs. (a) Methylation levels in male and female Bcl6-LKO (4 females, 4 males) and controls Bcl6-flox mice (6 females, 4 males); (b) Methylation levels in ARKO mice (with genetic and gonadal male sex and genital female sex) and control male and female littermates (3 females, 4 males, and 3 ARKO mice); (c) Methylation levels in wild type controls, heterozygous and homozygous ESR1KO mice (WT: 3 females, 7 males; HET: 4 females, 4 males, KO: 6 females, 4 males). [Extracted from the article]

The distal part of the mouse Chr 12 contains a cluster of reciprocally imprinted genes. Recently we found a grandparental origin-dependent, transmission-ratio distortion (TRD) in this region. The TRD resulted from postimplantation loss of embryos that inherited the distal Chr 12 alleles from the maternal grandfather. These data suggested that imprinting of one or more genes in this region was not uniformly well established or maintained in all the embryos. To elucidate the mechanism underlying such a variation, we examined the expression of two genes from the distal Chr 12 imprinted region, the maternally expressed gene 3/gene-trap locus 2 (Meg3/Gtl2), and the delta-like homolog 1 (Dlk1) gene. We demonstrated that the Meg3/Gtl2 gene had two major mRNA forms. One form, Meg3-proximal (Meg3p), contained exons 1–3. The second form, Meg3-distal (Meg3d) did not contain exons 1–3 and was present in oocytes and in 1- and 2-cell embryos. We observed cross-dependent and splice form-specific relaxation of imprinting of the Dlk1 and Meg3d, but not Meg3p. Expression patterns of Dlk1 and Meg3/Gtl2 in embryos from crosses between different mouse strains suggest that 1) imprinting of the Dlk1 and Meg3/Gtl2 genes is not strictly coordi- nated; 2) parental origin-dependent expression of these genes is under control of a strain-specific, cis-acting modifier located in a 1.5-Mb region that includes the Meg3/Gtl2-Dlk1 locus. Biallelic expression of Dlk1 and Meg3d did not affect embryo viability and, therefore, cannot be responsible for the lethal phenotypes in UPD12 embryos or for the transmission-ratio distortion. [ABSTRACT FROM AUTHOR]

Deviations from Mendelian 1:1 transmission ratio have been observed in mice and humans. With few exceptions, the mechanism leading to transmission-ratio distortion (TRD) remains obscure. We proposed that a genomic imprinting mechanism plays a key role in the genesis of grandparental origin-dependent TRD (Naumova et al. 2001). To further test this hypothesis, we analyzed the transmission of grandparental alleles at three imprinted regions of the mouse genome known to contain genes required for embryo development. We found and replicated moderate (58%: 42%) TRD in favor of grandmaternal alleles in the imprinted region of maternal distal Chromosome (Chr) 12 among female offspring. Comparison of transmission ratios at the distorted region of Chr 12 among 3-week-old mice with those in embryos suggests that the distortion in favor of grandmaternal alleles is owing to postimplantation embryo loss. The absence of grandparental origin-dependent TRD for maternal Chr 6 and 7 implies that the relationship between TRD and imprinting is complex. Most likely, multiple conditions are required for TRD to occur. [ABSTRACT FROM AUTHOR]