Gegenhuber, Bruno (April 2022) Epigenomic organization and activation of brain sex differences. PhD thesis, Cold Spring Harbor Laboratory.
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Abstract
The “Organizational-Activational Hypothesis”, the central dogma of neuroendocrinology, states that early-life (“organizational”) and adult (“activational”) gonadal hormone signaling drives sex differences in the mammalian brain. Early-life hormones irreversibly sculpt the development of the same neural circuits that adult hormones act upon to promote the display of sex-typical behaviors. Gonadal hormones bind nuclear hormone receptors, which principally act as transcription factors (TFs). Hence, the regulation of gene expression by hormone receptors in the brain comprises the molecular basis of the “Organizational-Activational Hypothesis”, and, accordingly, ensures the survival and propagation of most mammalian species. However, the genomic targets of gonadal hormone receptors in the brain, and their regulation during “organizational” and “activational” windows, have not been identified. Here, I utilize low-input and single-cell chromatin and transcriptomic profiling approaches to identify the genomic mechanisms specifying sex differences in the developing and adult mouse bed nucleus of the stria terminalis (BNST) – a central brain region in the limbic circuitry controlling sextypical behaviors. I find that male-specific activation of estrogen receptor α (ERα) on the day of birth drives sustained sex differences in gene regulation in the developing brain. Subsequently, testosterone (T) largely controls sex differences in gene regulation following puberty. Of note, adult gonadectomy ablates sex differences in chromatin accessibility, while estradiol (E2) replacement after gonadectomy leads to sex-shared genomic responses, revealing brain “organization” by early-life hormone signaling is reversible at the level of gene regulation. Together, I reveal the first genomic targets of a gonadal hormone receptor in the brain and define the molecular principles of the “Organizational-Activational Hypothesis”. I provide a compendia of sex-biased enhancers, genes, and neuron types across life stages that serve the basis for future functional investigation into the genomic encoding of social behavior.
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