Distinct roles of androgen receptor, estrogen receptor alpha, and BCL6 in the establishment of sex-biased DNA methylation in mouse liver

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 s...

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Bibliographic Details
Published in:Scientific reports 2021-07, Vol.11 (1), p.13766-13766, Article 13766
Main Authors: AlOgayil, Najla, Bauermeister, Klara, Galvez, Jose Hector, Venkatesh, Varun S., Zhuang, Qinwei Kim-wee, Chang, Matthew L., Davey, Rachel A., Zajac, Jeffrey D., Ida, Kinuyo, Kamiya, Akihide, Taketo, Teruko, Bourque, Guillaume, Naumova, Anna K.
Format: Article
Language:English
Subjects:
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Androgen receptors
Androgens
Bcl-6 protein
Bias
Demethylation
Deoxyribonucleic acid
DNA
DNA methylation
Estrogen receptors
Estrogens
Gene expression
Gene regulation
Hermaphrodites
Humanities and Social Sciences
Liver
multidisciplinary
Phenotypes
Science
Science (multidisciplinary)
Sex
Sexual dimorphism
Testes
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-93216-6