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Regional epigenetic differentiation of the Z Chromosome between sexes in a female heterogametic system.

ABSTRACT: In male heterogametic systems, the X Chromosome is epigenetically differentiated between males and females, to facilitate dosage compensation. For example, the X Chromosome in female mammals is largely inactivated. Relative to well-studied male heterogametic systems, the extent of epigenetic differentiation between male and female Z Chromosomes in female heterogametic species, which often lack complete dosage compensation, is poorly understood. Here, we examined the chromosomal DNA methylation landscapes of male and female Z Chromosomes in two distantly related avian species, namely chicken and white-throated sparrow. We show that, in contrast to the pattern in mammals, male and female Z Chromosomes in these species exhibit highly similar patterns of DNA methylation, which is consistent with weak or absent dosage compensation. We further demonstrate that the epigenetic differences between male and female chicken Z Chromosomes are localized to a few regions, including a previously identified male hypermethylated region 1 (MHM1; CGNC: 80601). We discovered a novel region with elevated male-to-female methylation ratios on the chicken Z Chromosome (male hypermethylated region 2 [MHM2]; CGNC: 80602). The MHM1 and MHM2, despite little sequence similarity between them, bear similar molecular features that are likely associated with their functions. We present evidence consistent with female hypomethylation of MHMs and up-regulation of nearby genes. Therefore, despite little methylation differentiation between sexes, extremely localized DNA methylation differences between male and female chicken Z Chromosomes have evolved and affect expression of nearby regions. Our findings offer new insights into epigenetic regulation of gene expression between sexes in female heterogametic systems.

SUBMITTER: Sun D

PROVIDER: S-EPMC6771406 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSex differences in pituitary growth hormone (GH) are well documented and coordinate maturation and growth. GH and its receptor are also produced in the brain where they may impact cognitive function and synaptic plasticity, and estradiol produces Gh sex differences in rat hippocampus. In mice, circulating estradiol increases Gh mRNA in female but not in male medial preoptic area (mPOA); therefore, additional factors regulate sexually dimorphic Gh expression in the brain. Thus, we hypothesized that sex chromosomes interact with estradiol to promote sex differences in GH. Here, we assessed the contributions of both estradiol and sex chromosome complement on Gh mRNA levels in three large brain regions: the hippocampus, hypothalamus, and cerebellum.MethodsWe used the four core genotypes (FCG) mice, which uncouple effects of sex chromosomes and gonadal sex. The FCG model has a deletion of the sex-determining region on the Y chromosome (Sry) and transgenic insertion of Sry on an autosome. Adult FCG mice were gonadectomized and given either a blank Silastic implant or an implant containing 17β-estradiol. Significant differences in GH protein and mRNA were attributed to estradiol replacement, gonadal sex, sex chromosome complement, and their interactions, which were assessed by ANOVA and planned comparisons.ResultsEstradiol increased Gh mRNA in the cerebellum and hippocampus, regardless of sex chromosome complement or gonadal sex. In contrast, in the hypothalamus, females had higher Gh mRNA than males, and XY females had more Gh mRNA than XY males and XX females. This same pattern was observed for GH protein. Because the differences in Gh mRNA in the hypothalamus did not replicate prior studies using other mouse models and tissue from mPOA or arcuate nucleus, we examined GH protein in the arcuate, a subdivision of the hypothalamus. Like the previous reports, and in contrast to the entire hypothalamus, a sex chromosome complement effect showed that XX mice had more GH than XY in the arcuate.ConclusionsSex chromosome complement regulates GH in some but not all brain areas, and within the hypothalamus, sex chromosomes have cell-specific actions on GH. Thus, sex chromosome complement and estradiol both contribute to GH sex differences in the brain.

Project description:Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a strong genetic susceptibility due to the high concordance in monozygotic (MZ) twins and a striking female predominance. Women with PBC manifest an enhanced X monosomy rate in peripheral lymphocytes and we thus hypothesized an X chromosome epigenetic component to explain PBC female prevalence. While most genes on the female inactive X chromosome are silenced by promoter methylation following X chromosome inactivation (XCI), approximately 10% of X- linked genes exhibit variable escape from XCI in healthy females. This study was designed to test the hypothesis that susceptibility to PBC is modified by one or more X-linked gene with variable XCI status. Peripheral blood mRNA and DNA samples were obtained from a unique cohort of MZ twin sets discordant and concordant for PBC. Transcript levels of the 125 variable XCI status genes was determined by quantitative RT-PCR analysis and two genes (CLIC2 and PIN4) were identified as consistently downregulated in the affected twin of discordant pairs. Both CLIC2 and PIN4 demonstrated partial and variable methylation of CpG sites within 300 bp of the transcription start site that did not predict the XCI status. Promoter methylation of CLIC2 manifested no significant difference between samples and no significant correlation with transcript levels. PIN4 methylation showed a positive trend with transcription in all samples but no differential methylation was observed between discordant twins. A genetic polymorphism affecting the number of CpG sites in the PIN4 promoter did not impact methylation or transcript levels in a heterozygous twin pair and showed a similar frequency in independent series of unrelated PBC cases and controls. Our results suggest that epigenetic factors influencing PBC onset are more complex than methylation differences at X-linked promoters and variably 3 inactivated X-linked genes may be characterized by partial promoter methylation and biallelic transcription.

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Regional epigenetic differentiation of the Z Chromosome between sexes in a female heterogametic system.

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