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

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. Obesity risk may be largely determined by epigenetic development of the brain during early life.

近期的全基因组关联研究证实了有关发育编程的经典研究，表明肥胖主要是一种神经发育性疾病，在关键的个体发育窗口期受营养的强烈影响。表观遗传机制调控神经发育；然而，对于它们在建立和维持大脑能量平衡回路中的作用知之甚少。我们在跨越肥胖风险发育编程的一个既定关键窗口期关闭的时间点，从雄性和雌性小鼠下丘脑弓状核（能量平衡调节的关键部位）生成了神经元和神经胶质的甲基化组和转录组。我们发现，出生后的表观遗传成熟具有明显的细胞类型和性别特异性，且发生在人类体重指数遗传力富集的基因组区域。我们的研究结果为肥胖发育编程的有限个体发育窗口期以及性别差异敏感性提供了一种可能的解释，并为能量平衡发育编程的表观遗传分析提供了丰富的资源。 肥胖风险可能在很大程度上由生命早期大脑的表观遗传发育所决定。