Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index

Authors: MACKAY, HARRY - Baylor College Of Medicine; GUNASEKARA, CHATHURA - Baylor College Of Medicine; YAM, KIT-YI - Baylor College Of Medicine; SRISAI, DOLLADA - Vanderbilt University; YALAMANCHILI, HARI - Children'S Nutrition Research Center (CNRC); LI, YUMEI - Baylor College Of Medicine; CHEN, RUI - Baylor College Of Medicine; COARFA, CRISTIAN - Baylor College Of Medicine; WATERLAND, ROBERT - Baylor College Of Medicine

Submitted to: Science Advances
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/10/2022
Publication Date: 9/28/2022
Citation: MacKay, H., Gunasekara, C.J., Yam, K., Srisai, D., Yalamanchili, H.K., Li, Y., Chen, R., Coarfa, C., Waterland, R.A. 2022. Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index. Science Advances. 8(39). https://doi.org/10.1126%2Fsciadv.abo3991.
DOI: https://doi.org/10.1126%2Fsciadv.abo3991

Interpretive Summary: Obesity has emerged as a major global health issue, affecting over 2 billion people, and contributing significantly to poor health worldwide. Research indicates that nutrition during critical early-life stages can have long-lasting effects on energy balance regulation, increasing the risk of obesity. This concept, known as developmental programming, suggests that obesity should be viewed as a neurodevelopmental disease. The success of population-level interventions in preventing neural tube defects provides a model for primary prevention of obesity. Understanding developmental epigenetics, which involves the regulation of gene expression patterns during development, particularly within the hypothalamus and other brain regions, is crucial for effective interventions to prevent obesity. Developmental programming of energy balance is characterized by plasticity limited to specific developmental periods and sex-specific effects. This study focusses on sex-specific differences and analyzed the epigenetic maturation in the hypothalamic arcuate nucleus (ARH), a critical region involved in energy balance regulation. We found significant sex differences in the epigenetic maturation of the ARH, consistent with well-known anatomical and functional sexual dimorphisms in the hypothalamus. These findings provide insights into the function of postnatal epigenetic development and offer a framework for understanding the developmental factors influencing obesity risk. The study stimulates further research on developmental neuroepigenetics and identify vulnerable developmental processes to develop effective interventions for preventing obesity.

Technical Abstract: Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and occurs in genomic regions enriched for heritability of body mass index in humans. Our results offer a potential explanation for both the limited ontogenic windows for and sex differences in sensitivity to developmental programming of obesity and provide a rich resource for epigenetic analyses of developmental programming of energy balance.