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The Critical Role of Iron Metabolism in KDM3A-mediated Epigenetic Determination of Male Sex

By Stuart P. Atkinson, Ph.D.

January 15, 2026

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A Link Between KDM3A, Iron, and Sex?

Sexually bipotential gonads differentiate into the testes – the part of the male reproductive system that produces spermatozoa and hormones - during sex determination in mammals thanks, in part, to the expression of the testis-determining gene Sry (Sinclair et al. and Koopman et al.). This all-important Y-chromosomal sex-determining gene remains under tight epigenetic regulation in specific gonadal somatic cells (Kashimada & Koopman), thanks in part to the JmjC-family H3K9 demethylase KDM3A (Stévant et al.). The activity of this critical epigenetic enzyme switches the chromatin landscape of the Sry locus from a transcriptionally repressive to a transcriptionally permissive state to allow male sex determination (Kuroki et al., 2013 and Kuroki et al., 2017). Of note, the proper function of the JmjC-family histone demethylases requires iron (Fe²⁺), which is itself tightly regulated under physiological conditions (Galy et al.). Researchers from the laboratory of Makoto Tachibana (Osaka University) sought to investigate any potential connections between these seemingly disparate elements with these studies in mind; now, their fascinating new Nature study describes the unexpected link between iron metabolism, H3K9 histone demethylation by KDM3A, and male sex determination in mice (Okashita et al.).

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A Lack of Iron Impacts KDM3A-mediated H3K9 Demethylation at the Sry Gene Locus and Sex Determination

In brief, the team first identified a gene and protein expression profile that favored Fe²⁺ accumulation in pre-Sertoli cells of mouse embryonic gonads during the sex-determining period, and then employed inductively coupled plasma mass spectrometry (ICP-MS) to confirm the presence of both haem and non-haem iron. The authors then established mice lacking iron-metabolism genes to evaluate the contribution of iron metabolism to the epigenetic regulation of Sr expression by selectively disrupting Tfrc gene expression in gonadal somatic cells before sex determination. Tfrc encodes the Transferrin receptor protein 1 (TfR1) protein, which plays a pivotal role in cellular iron incorporation via the internalization of the transferrin–iron complex (Qian et al.). Overall, compromised H3K9 demethylation following TfR1 depletion suggested a requirement for correct iron balance in embryonic gonadal somatic cells for normal male sex determination in vivo and implicated the TfR1-mediated iron-incorporating pathway in the KDM3A-mediated epigenetic regulation of Sry. The authors next revealed that sequestering iron in cultured XY gonads via treatment with an iron-specific chelator prompted a reduction in KDM3A-mediated H3K9 demethylation at the Sry locus, which almost completely abolished gene expression and, fascinatingly, caused the cultured XY gonads to begin to express known ovarian markers.

Subsequent in vivo experiments revealed that pharmaceutical suppression of available iron in pregnant mice, achieved by administering an oral iron chelator, prompted male-to-female gonadal sex reversal in some offspring, highlighting the critical role of iron metabolism in male sex determination. The long-term feeding of pregnant mice with a low-iron diet combined with a heterozygous variant of Kdm3a (phenotypically normal but sensitized to compromised H3K9 demethylation; no observable effect alone) suppressed Sry expression and caused male-to-female sex reversal in some offspring, which demonstrated a connection between maternal dietary iron and fetal developmental outcomes.

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The Influence of Iron Beyond KDM3A-mediated H3K9 Demethylation?

Overall, this fascinating study reveals that activating iron/Fe²⁺-associated pathways in developing gonads during sex determination facilitates KDM3A-mediated H3K9 demethylation at the Sry gene locus and that maternal iron deficiency causes male-to-female sex reversal in some developing embryos in utero. Given this exciting finding and the fact that additional JmjC-domain containing histone demethylases and ten-eleven translocation (TET) methylcytosine dioxygenases (also involved in DNA demethylation) require Fe²⁺ for their activity, the authors suggest that investigating how iron deficiency alters gene-expression profiles during the developmental process by altering histone modification and DNA methylation status may represent a fertile field of exploration.

Can Active Motif lend a helping hand in related research? Check out our wide range of JMJD/KDM products, JARID/KM products, JHDM/KBM products, additional KDM products, and TET products to find out!

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

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