TEMPORAL EPIGENETIC REGULATION IN HUMAN HYPOTHALAMIC NEURONS AND BODY WEIGHT

The hypothalamus is the brain hub that regulates energy homeostasis. The genetic and molecular basis of thisregulation in humans is not well understood as access to this tissue is a major barrier and available onlypostmortem. To overcome the barrier of limited tissue access, we are generating induced pluripotent stem cell(iPSC)-derived neuronal cultures that recapitulate many of the features of hypothalamic neurons from thearcuate nucleus, including by benchmarking this in vitro model to in vivo events that are pivotal in hypothalamicdevelopment. We will use this human model and state of the art high throughput assays to test our hypothesisthat non-coding genetic variants associated with obesity measures and body weight regulation impact on thesetraits secondarily through epigenetic regulation which is dynamic across hypothalamic development. We willemploy genome editing techniques such as CRISPR in our human cells to experimentally assess physiologiceffects of variants identified to influence chromatin status of obesity associated loci. The public health impactof all functional variants will then be assessed using data from large, multi-ethnic epidemiologic cohorts.These studies will represent the first attempt at establishing the epigenetic architecture of human hypothalamicneuronal cells and serve as a bioresource for understanding diseases linked to alterations in energyhomeostasis. A unique component is the evaluation at multiple time points during development, thus providinga critical catalogue of the human epigenome at stages representing fetal development. We anticipate that theepigenetic map will differ from that in adult brain and will vary temporally. We also anticipate that genesassociated with body weight regulation will cluster into distinct chromatin accessibility patterns that differ overtime. Discovery of epigenetic mechanisms connected to genetic liability will identify potential underlying factorsbehind both heritable and diet-induced obesity and potential therapeutic means by which the epigeneticmechanisms that influence disease susceptibility can be reversed.