Distinct roles of androgen receptor, estrogen receptor alpha, and BCL6 in the establishment of sex-biased DNA methylation in mouse liver.
Distinct roles of androgen receptor, estrogen receptor alpha, and BCL6 in the establishment of sex-biased DNA methylation in mouse liver.
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DOI：
10.1038/s41598-021-93216-6
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发表时间：
2021-07-02
影响因子：
4.6
通讯作者：
Naumova AK
中科院分区：
文献类型：
--
作者：
AlOgayil N;Bauermeister K;Galvez JH;Venkatesh VS;Zhuang QK;Chang ML;Davey RA;Zajac JD;Ida K;Kamiya A;Taketo T;Bourque G;Naumova AK
基因调控中的两性二态性，包括DNA甲基化，是表型中两性二态性的主要驱动因素。然而，性如何以及何时影响DNA甲基化的问题仍未得到解决。最近，我们使用具有不同遗传和表型性别组合的小鼠，确定了依赖于性别表型的性别相关差异甲基化区域（sDMRs）。聚焦于一组已验证的性别表型依赖的男性和女性偏倚sDMRs，我们测试了肝脏甲基化中性别偏倚的发育动力学以及雄激素受体、雌激素受体α或转录抑制因子Bcl6基因突变的影响。同时携带单侧卵巢和对侧睾丸的真正雌雄同体也进行了测试。我们的数据显示，甲基化的性别偏倚与sdmr近端基因表达的性别偏倚一致或紧随其后，这表明基因表达的性别偏倚可能是某些sDMRs去甲基化所必需的。AR的整体消融、ESR1或肝脏特异性BCL6的缺失都会改变sDMR甲基化，而卵巢和睾丸的存在则会延迟雌雄同体中雄性型甲基化水平的建立。此外，BCL6 - lko在表达和甲基化之间表现出分离，这表明BCL6在基因内sDMRs的去甲基化中起着独特的作用。
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.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
通讯作者：
Itzkovitz S
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
9.2
作者：
Bourgey, Mathieu;Dali, Rola;Bourque, Guillaume
通讯作者：
Bourque, Guillaume
影响因子：
30.8
作者：
COWARD, P;NAGAI, K;LAU, YFC
通讯作者：
LAU, YFC
影响因子：
5.3
作者：
De Mees, C;Laes, JF;Szpirer, C
通讯作者：
Szpirer, C