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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 \u03b2 (ER\u03b2) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>Cyp19a1<\/jats:italic>\n                      (aromatase) and\n                      <jats:italic>Esr2<\/jats:italic>\n                      (ER\u03b2) expression. To assess this, pharmacological inhibition of DNA methylation, using zebularine, as well as Chromatin Immunoprecipitation (ChIP-qPCR) assays were performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>Cyp19a1<\/jats:italic>\n                      promoter in male cultures that was not observed in females. No significant enrichment of the examined epigenetic marks was detected at the\n                      <jats:italic>Esr2<\/jats:italic>\n                      promoter.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Acetylation of histone H4 contributes to promoting the higher\n                      <jats:italic>Cyp19a1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-026-00854-4","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T08:57:59Z","timestamp":1771491479000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sex chromosome\u2013dependent epigenetic regulation underlies sex-specific H4 acetylation at the aromatase promoter in the developing mouse amygdala"],"prefix":"10.1186","volume":"17","author":[{"given":"C.","family":"Sosa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. 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Ferreyra (Res. 004\/2021), following national and international regulations. The procedures performed at the Instituto Cajal followed the European Parliament and Council Directive (2010\/63\/EU) and the Spanish regulation (R.D. 53\/2013 and Ley 6\/2013, 11th June) on the protection of animals for experimental use and were approved by the Comit\u00e9 de \u00c9tica de Experimentaci\u00f3n Animal del Instituto Cajal, and by the Consejer\u00eda del Medio Ambiente y Territorio (Comunidad de Madrid, PROEX 059.5\/21).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"57"}}