Epigenetic machinery of developing brain is modulated by sex chromosomes in a region-specific manner

SOSA, C.; CABRERA ZAPATA, L.E.; CAMBIASSO, M.J.

Belem

Congreso; 3rd Congress of the Federation of Latin American and Caribbean Neuroscience Societies (FALAN); 2022

Sociedade Brasileira de Neurociencias e Comportamento

INTRODUCTION Sex differences described in certain regions of mouse brain are caused by two principal factors, 1- a hormonal environment generated by the secretion of androgens of fetal testis during the critical period (E18 - PN10), and 2- a genetic factor derived from the differential expression of genes carried on sex chromosomes. In both contexts, the epigenetic mechanisms have been proposed as potentially involved in establish and maintain genome marks generating a sexually dimorphic gene expression. Several X/Y linked genes encoding transcriptional regulator proteins have the potential to mediate chromatin changes and regulate autosomal gene expression. Furthermore, sex differences in gene expression have been observed in the hypothalamus and the amygdala before of critical period of sexual differentiation of the brain because of sex chromosome complement. OBJECTIVES We focus on the study of the regulatory machinery involved in the establishment of epigenetic marks to understand the origin of sex differences observed in gene expression during early development indifferent brain regions. METHODS In according to our aim, we evaluated the expression of epigenetic modifiers such as DNAmethyltransferases (Dnmts), and histone deacetylases (Hdacs) in the “four core genotypes” mice (approved by Ethics Committee, Res 04/2021). This mouse model combines a deletion of the testis-determining gene Sry from the Y chromosome with the subsequent insertion of a Sry transgene onto anautosome, so, the Y chromosome and the Sry transgene segregates independently, and four types of offspring are produced: XX and XY females (without Sry on the Y chromosome) and XXSry and XYSry male mice (both with Sry in an autosome). It allows the isolated evaluation of gonadal sex, sex chromosome complement, and their interaction. By RT-qPCR, we have analyzed the mRNA expression of Dnmt1, Dnmt3a, Dnmt3b, and Hdac1, Hdac2, Hdac4, Hdac6, Hdac8 in E15 tissue of amygdala and hypothalamus; and we have also evaluated the cerebral cortex. RESULTS We found that gene expression is specific of each examined area, thus, Dnmt3a and Dnmt3b, as well asHdac2 and Hdac8 expression levels were higher in amygdala derived from XX embryos compared to XY(p