Early sex differences in histone methytransferase EZH2 expression in developing hypothalamus of the mouse brain

VILLAREAL, M.; BIGARANI, R.; SOSA, C.; CABRERA ZAPATA, L.E.; CISTERNAS, C.D.; CAMBIASSO, M.J.

Encuentro; XXXVII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2022

Sociedad Argentina de Investigación en Neurociencias (SAN)

In mammals, the primary agents causing phenotypic sex differences are encoded by sex chromosomes. Many of X-and Y-linked genes are epigenetic modifiers and pivotal evidence in past 7 years implicates epigenetic mechanisms as mediators in brain sexual differentiation. We have recently demonstrated that X‑linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons through a direct regulation of Neurogenin 3. Kdm6a interacts with numerous epigenetic modifiers, such as histone methyltransferases (HMT), implying that both epigenetic marks could act together, influencing each other in a context-dependent manner, writing a histone crosstalk language. Since H3K27 methylation regulate Ngn3 we first evaluated the mRNA expression of the HMT enzymes EZH1/2 in the hypothalamus of male and female mice at embryonic day 15 by qPCR. We found sex specific expression of Ezh2, higher in males than in females (p = 0.01). We next used the Four Core Genotype Mouse Model to evaluate a direct regulation of sex chromosomes (XX vs XY) independently of gonadal type. No differences were observed between genotypes (p > 0.05). Our results suggest that early sex differences in Ezh2 enzyme could determine a sexually dimorphic crosstalk between posttranslational histone modifications acting on H3K27 residues during development. Current experiments are evaluating the effect of Ezh2 inhibition on Ngn3 expression in neuronal hypothalamic cultures.