Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY Most neurological and neurodevelopmental disorders are sex-biased in incidence or severity. To understand why one sex may be vulnerable to a disease, it is important to understand brain development in both sexes. Mood, cognition, and other processes are regulated by estrogen receptor (ER) a neurons. Female have increased number of ERa neurons in the hypothalamus, compared to males. This is an example of a sex difference in neurochemical phenotype, the most common type of sex difference in the brain. Despite this, little is known on the mechanisms controlling their development. Our research suggests that epigenetic mechanisms underlie sex differences in neurochemical phenotype that may contribute to sex biases in disease. Inhibiting DNA methylation in the brains of newborn mice reduces sex differences in ERa in the preoptic area (POA) and the ventrolateral area of the ventromedial hypothalamus (VMHvl) at weaning. We recently reported that DNA methyltransferases (Dnmts; which add methyl marks) and ten eleven translocases (Tets; which remove methyl marks), peak shortly after birth in both sexes in the hypothalamus. Additionally, females have higher expression of Dnmts, while males have higher expression of Tets during this period. This suggests that DNA methylation and hydroxymethylation are dynamic and sex- biased during neonatal brain development. Interestingly, both sexes have an equally high number of ERa cells in the VMHvl at birth, but only in males, it decreases 50% by weaning. This proposal will test the hypothesis that ERa cells in males, but not females, accumulate DNA methylation marks during postnatal development which establishes the sex difference. The F99 phase will test 1) whether sub-populations of ERa cells with functional roles are sensitive to neonatal inhibition of DNA methylation using single-molecule fluorescent in situ hybridization and 2) whether specific sub-populations down-regulate ERa expression across development (Aim 2a). Lastly, using methylated and hydroxymethylated DNA immunoprecipitation sequencing, it will test the hypotheses that there are global sex differences and developmental changes in the epigenome, and specifically, that the ERa promoter in males has increased levels of DNA methylation compared to females (Aim 2b). The proposed study will help the candidate, Laura Cortes, achieve her goal of becoming a tenure-track professor at an R1 institution. This proposal will provide training in cutting-edge techniques, such as sm-FISH and epigenomic sequencing, to investigate how DNA methylation regulates neurochemical phenotype in both sexes. The Neuroscience Institute at Georgia State University is an ideal environment given the 1) access to the expertise of reputed neuroendocrinologists and state-of-the-art tools, 2) collaborative intra-departmental and inter-institutional atmosphere, and 3) the plethora of career development opportunities. Completion of the training plan described in this proposal will ensure the development of a well-rounded and successful scientist capable of transitioning into an independent investigator.
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