Department of Human Genetics, McGill University, Montréal, QC, Canada.
Canadian Centre for Computational Genomics, Montréal, QC, Canada.
Sci Rep. 2021 Jul 2;11(1):13766. doi: 10.1038/s41598-021-93216-6.
Sexual dimorphism in gene regulation, including DNA methylation, is the main driver of sexual dimorphism in phenotypes. However, the questions of how and when sex shapes DNA methylation remain unresolved. Recently, using mice with different combinations of genetic and phenotypic sex, we identified sex-associated differentially methylated regions (sDMRs) that depended on the sex phenotype. Focusing on a panel of validated sex-phenotype dependent male- and female-biased sDMRs, we tested the developmental dynamics of sex bias in liver methylation and the impacts of mutations in the androgen receptor, estrogen receptor alpha, or the transcriptional repressor Bcl6 gene. True hermaphrodites that carry both unilateral ovaries and contralateral testes were also tested. Our data show that sex bias in methylation either coincides with or follows sex bias in the expression of sDMR-proximal genes, suggesting that sex bias in gene expression may be required for demethylation at certain sDMRs. Global ablation of AR, ESR1, or a liver-specific loss of BCL6, all alter sDMR methylation, whereas presence of both an ovary and a testis delays the establishment of male-type methylation levels in hermaphrodites. Moreover, the Bcl6-LKO shows dissociation between expression and methylation, suggesting a distinct role of BCL6 in demethylation of intragenic sDMRs.
性别在基因调控中的二态性，包括 DNA 甲基化，是表型性别二态性的主要驱动因素。然而，性是如何以及何时塑造 DNA 甲基化的问题仍未解决。最近，我们使用具有不同遗传和表型性别的组合的小鼠，确定了依赖于性表型的性相关差异甲基化区域（sDMR）。我们关注一组经过验证的依赖于性表型的雄性和雌性偏置 sDMR，测试了肝甲基化中性别偏置的发育动态以及雄激素受体、雌激素受体 alpha 或转录抑制因子 Bcl6 基因突变的影响。还测试了携带单侧卵巢和对侧睾丸的真正雌雄同体。我们的数据表明，甲基化的性别偏置要么与 sDMR 近端基因表达的性别偏置一致，要么紧随其后，这表明基因表达的性别偏置可能是某些 sDMR 去甲基化所必需的。AR、ESR1 或 BCL6 的全局缺失都会改变 sDMR 甲基化，而同时存在卵巢和睾丸会延迟雌雄同体中雄性类型甲基化水平的建立。此外，Bcl6-LKO 显示出表达和甲基化之间的分离，表明 BCL6 在基因内 sDMR 去甲基化中具有独特的作用。
