Okashita Naoki, Maeda Ryo, Kuroki Shunsuke, Sasaki Kyona, Uno Yoko, Koopman Peter, Tachibana Makoto
Laboratory of Epigenome Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Nature. 2025 Jun 4. doi: 10.1038/s41586-025-09063-2.
Ferrous iron (Fe) is essential in all eukaryotic cells for various oxidoreductase reactions, including the demethylation of DNA and proteins. Histone demethylation is required for normal epigenetic regulation of the Y-chromosomal sex-determining gene Sry in developing gonads during male sex determination. Here we investigate the potential connection between iron metabolism, histone demethylation and sex determination in mammals. We found that Fe-producing pathways are substantially activated in mouse embryonic gonads during the sex-determining period. Chelation of iron in cultured XY gonads reduced the level of KDM3A-mediated H3K9 demethylation of Sry, mostly abolished Sry expression and caused the gonads to express ovarian markers. In vivo, conditional deletion of the gene Tfrc-which is required for iron incorporation-in fetal XY gonadal somatic cells, or acute pharmaceutical suppression of available iron in pregnant mice, resulted in male-to-female gonadal sex reversal in a proportion of offspring, highlighting the pivotal role of iron metabolism in male sex determination. Finally, long-term feeding of pregnant mice with a low-iron diet, when combined with a heterozygous variant of Kdm3a that by itself has no observable effect, suppressed Sry expression and caused male-to-female sex reversal in some of the progeny, revealing a connection between maternal dietary iron and fetal developmental outcomes.
亚铁离子（Fe）在所有真核细胞中对于各种氧化还原酶反应至关重要，包括DNA和蛋白质的去甲基化。在雄性性别决定过程中，发育中的性腺中Y染色体性别决定基因Sry的正常表观遗传调控需要组蛋白去甲基化。在此，我们研究了哺乳动物中铁代谢、组蛋白去甲基化和性别决定之间的潜在联系。我们发现，在性别决定期，小鼠胚胎性腺中的铁生成途径被大量激活。在培养的XY性腺中螯合铁会降低KDM3A介导的Sry的H3K9去甲基化水平，几乎完全消除Sry的表达，并使性腺表达卵巢标志物。在体内，条件性缺失胎儿XY性腺体细胞中铁掺入所需的基因Tfrc，或对怀孕小鼠进行急性药物性铁抑制，导致一部分后代出现雄性到雌性的性腺性反转，突出了铁代谢在雄性性别决定中的关键作用。最后，给怀孕小鼠长期喂食低铁饮食，当与本身没有可观察到影响的Kdm3a杂合变体结合时，会抑制Sry表达，并在一些后代中导致雄性到雌性的性反转，揭示了母体饮食中的铁与胎儿发育结果之间的联系。
