Epigenetics and Sex Differences in the Brain
Exposure to gonadal steroids early in life has lasting (in many cases, permanent) effects on the brain. The nature of this “cellular memory” for hormone exposure has been mysterious but recent work demonstrates that epigenetics (literally, “above” or “on top of” genetics) are involved.
Epigenetic modifications of chromatin play crucial roles in the differentiation of cell type by affecting gene expression without changing the underlying DNA code. The two best-understood types of epigenetic marks are the methylation of DNA and covalent modifications of the histone proteins that DNA wraps around (e.g., acetylation or methylation of histone tails).
We hypothesized that epigenetic modifications are required for the development of neural sex differences, and have taken two approaches to test this idea: 1) blocking specific epigenetic processes during the critical period for sexually dimorphic brain development; and 2) genome-wide examinations of sex differences in the distribution of epigenetic modifications.
We find that a transient disruption in histone acetylation at birth leads to lasting changes in a well-studied sex difference in the bed nucleus of the stria terminalis (BNST; Murray et al., 2009; McCarthy et al., 2009). Genome-wide examinations of sex differences in epigenetic marks in the BNST were performed in collaboration with the laboratories of Dr. Schahram Akbarian at the Mt. Sinai School of Medicine and Dr. Eric Villain at UCLA. We find sex differences in the distribution of H3K4me3 (the addition of three methyl groups to histone 3 at lysine 4), an epigenetic mark that is often associated with the transcription start sites of active genes (Shen et al., 2015). We also find that neonatal testosterone exposure alters DNA methylation at several hundred genes in the BNST of the mouse brain, and that these effects emerge late, i.e., well after the hormone exposure (Ghahramani et al., 2014). Currently, we are exploring the effects of blocking DNA methylation on sex differences in gene expression in the brain.
Shen EY, Ahern TH, Cheung I, Straubhaar J, Dincer A, Houston I, de Vries GJ, Akbarian S, Forger NG. 2015. Epigenetics and sex differences in the brain: A Genome-Wide Comparison of Histone-3 Lysine-4 Trimethylation (H3K4me3) in Male and Female Mice. Experimental Neurology 268: 21-29.
Ghahramani NM, Ngun TC, Chen P.-Y, Tian Y, Krishnan S, Muir S, Rubbi L, Arnold AP, De Vries GJ, Forger NG, Pellegrini M, Vilain E. 2014. The effects of perinatal testosterone exposure on the brain DNA methylome of the mouse brain are late-emerging. Biology of Sex Differences 5: 8.
Murray EK, Varnum MM, Fernandez JL, de Vries GJ, Forger NG. 2011. Effects of neonatal treatment with valproic acid on vasopressin immunoreactivity and olfactory behaviour in mice.
Journal of Neuroendocrinology 23: 906-914.
McCarthy MM, Auger AP, Bale TL, De Vries GJ, Dunn GA, Forger NG, Murray EK, Nugent BM, Schwarz JM, Wilson ME. 2009. The epigenetics of sex differences in the brain. Journal of Neuroscience 29:12815-12823.
Murray EK, Hien A, de Vries GJ, Forger NG. 2009. Epigenetic control of sexual differentiation of the bed nucleus of the stria terminalis. Endocrinology 150:4241-4247.