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Background <p>Sexual differentiation of the brain is a complex ontogenetic process orchestrated by genetic and hormonal influences, leading to sex‑specific physiological and behavioral traits in adulthood. In mammals, the sex chromosome complement (SCC) contributes to this process by encoding unequal genetic information in XX and XY cells. Furthermore, SCC upregulates aromatase and estrogen receptor β (ERβ) expression in amygdala neurons of XY compared to XX embryos at embryonic day (E) 14. These molecules are critically implicated in the steroid-dependent programming of neural circuits during the subsequent critical window of sexual differentiation (E17-PN10). Since epigenetic mechanisms play a key role in specific target gene expression forming a layer of gene regulation, we aimed to contribute to a better understanding of their impact on the sexual differentiation of the brain.</p> Methods <p>Four Core Genotypes mouse model was employed to study the epigenetic machinery involved in DNA methylation and histone deacetylation in different brain regions (amygdala, hypothalamus, and cortex) to elucidate the underlying epigenetic landscape at E14 by RT-qPCR. Amygdala primary neuronal cultures were then established to evaluate the epigenetic regulation of <i>Cyp19a1</i> (aromatase) and <i>Esr2</i> (ERβ) expression. To assess this, pharmacological inhibition of DNA methylation, using zebularine, as well as Chromatin Immunoprecipitation (ChIP-qPCR) assays were performed.</p> Results <p>Sex-specific expression of DNA methyltransferases 3a and 3b, along with histone deacetylases 2 and 8, was higher in XX than XY embryos in a region- and developmental stage- dependent manner. Pharmacological inhibition of DNA methylation did not significantly alter aromatase expression in male or female amygdala neuronal cultures under the conditions tested. However, ChIP-qPCR assays revealed a selective enrichment of Acetyl-H4 at the <i>Cyp19a1</i> promoter in male cultures that was not observed in females. No significant enrichment of the examined epigenetic marks was detected at the <i>Esr2</i> promoter.</p> Conclusions <p>Acetylation of histone H4 contributes to promoting the higher <i>Cyp19a1</i> expression previously observed in male neurons. Our findings support a model in which SCC plays a role in the epigenetic regulation of aromatase, a key enzyme involved in hormone-driven sexual differentiation of the male brain. Furthermore, the presence of two X chromosomes shapes a distinct epigenetic landscape in the brain during early development, highlighting the influence of chromosomal sex on the neurodevelopmental programming.</p>

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Sex chromosome–dependent epigenetic regulation underlies sex-specific H4 acetylation at the aromatase promoter in the developing mouse amygdala

  • 期刊论文

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  • 发表日期：

    2026年2月19日

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  • C. Sosa,
  • L. E. Cabrera-Zapata,
  • C. D Cisternas,
  • M. A. Arevalo,
  • M. J. Cambiasso

摘要

Background

Sexual differentiation of the brain is a complex ontogenetic process orchestrated by genetic and hormonal influences, leading to sex‑specific physiological and behavioral traits in adulthood. In mammals, the sex chromosome complement (SCC) contributes to this process by encoding unequal genetic information in XX and XY cells. Furthermore, SCC upregulates aromatase and estrogen receptor β (ERβ) expression in amygdala neurons of XY compared to XX embryos at embryonic day (E) 14. These molecules are critically implicated in the steroid-dependent programming of neural circuits during the subsequent critical window of sexual differentiation (E17-PN10). Since epigenetic mechanisms play a key role in specific target gene expression forming a layer of gene regulation, we aimed to contribute to a better understanding of their impact on the sexual differentiation of the brain.

Methods

Four Core Genotypes mouse model was employed to study the epigenetic machinery involved in DNA methylation and histone deacetylation in different brain regions (amygdala, hypothalamus, and cortex) to elucidate the underlying epigenetic landscape at E14 by RT-qPCR. Amygdala primary neuronal cultures were then established to evaluate the epigenetic regulation of Cyp19a1 (aromatase) and Esr2 (ERβ) expression. To assess this, pharmacological inhibition of DNA methylation, using zebularine, as well as Chromatin Immunoprecipitation (ChIP-qPCR) assays were performed.

Results

Sex-specific expression of DNA methyltransferases 3a and 3b, along with histone deacetylases 2 and 8, was higher in XX than XY embryos in a region- and developmental stage- dependent manner. Pharmacological inhibition of DNA methylation did not significantly alter aromatase expression in male or female amygdala neuronal cultures under the conditions tested. However, ChIP-qPCR assays revealed a selective enrichment of Acetyl-H4 at the Cyp19a1 promoter in male cultures that was not observed in females. No significant enrichment of the examined epigenetic marks was detected at the Esr2 promoter.

Conclusions

Acetylation of histone H4 contributes to promoting the higher Cyp19a1 expression previously observed in male neurons. Our findings support a model in which SCC plays a role in the epigenetic regulation of aromatase, a key enzyme involved in hormone-driven sexual differentiation of the male brain. Furthermore, the presence of two X chromosomes shapes a distinct epigenetic landscape in the brain during early development, highlighting the influence of chromosomal sex on the neurodevelopmental programming.