Skip to main content
ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Research Project #426617

Research Project: Epigenetics of Stem Cells, Obesity, and Diabetes

Location: Children's Nutrition Research Center

Project Number: 3092-51000-064-030-S
Project Type: Non-Assistance Cooperative Agreement

Start Date: Apr 1, 2014
End Date: Mar 31, 2019

Objective:
Objective 1: Determine if nutritional programming of body weight regulation occurs by inducing specific alterations in hypothalamic DNA methylation using approaches such as DNA methylation profiling by genome-wide bisulfite-sequencing and methylation-specific amplification sequencing, coupled with techniques for separation of neuronal and glial DNA, and microdissection of specialized functional regions of the hypothalamus. Subobjective 1A: Characterize changes in DNA methylation within the arcuate nucleus of the hypothalamus (ARH) before, during, and after the critical period for the formation of projections from the ARH to the paraventricular nucleus of the hypothalamus (PVH). Subobjective 1B: Establish whether leptin alters epigenetic events within the ARH during postnatal formation of ARH > PVH projections. Subobjective 1C: Determine if the persistent effects of postnatal overnutrition on body weight regulation are mediated by induced cell-type specific epigenetic changes in the ARH or PVH. Subobjective 1D: Perform a genome-wide screen for obesity-related metastable epialleles in humans. Objective 2: Establish if DNA methylation controls selective gene activation and silencing at distinct stages of intestinal epithelial stem cell development using genetically modified mice with application of whole genome shotgun sequencing or high resolution interrogation of epigenomes. Subobjective 2A: Use intestinal epithelial stem cells (IESCs) isolated at distinct developmental time-points to identify genomic loci that undergo developmentally programmed changes in DNA methylation. Subobjective 2B: Determine if the identified changes in DNA methylation are associated with developmental-stage and cell-type specific gene expression. Objective 3: Study diet during critical developmental period to assess if it affects epigenetic mechanisms in intestinal epithelial stem cells to modulate their lifelong role in self-renewal and differentiation. Determine whether dietary factors such as folate, vitamin B12, betaine, and choline permanently alter DNA methylation and gene expression in these stem cells and characterize the nutrient impact on stem cell differentiation and proliferation. Subobjective 3A: Determine whether dietary factors transiently or permanently alter DNA methylation and gene expression in IESCs. Subobjective 3B: Characterize the functional impact of host-dietary supplementation on proliferation and differentiation of IESCs. Objective 4: Objective no longer being addressed due to investigator departure.

Approach:
Metabolic programming occurs when nutrition and other environmental exposures affect prenatal or early postnatal development, causing structural or functional changes that persist to influence health throughout life. Epigenetic mechanisms regulate cell-type specific gene expression, are established during development, and persist for life. Importantly, nutrition during prenatal and early postnatal development can induce epigenetic changes that persist to adulthood. Researchers will focus on DNA methylation because this is the most stable epigenetic mechanism. The inherent cell-type specificity of epigenetic regulation motivates development of techniques to isolate and study specific cell types of relevance to a certain disease. For this reason our research integrates both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand metabolic programming of body weight regulation. Mouse models will also be used to investigate epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize their involvement in metabolic programming related to obesity, inflammation, and gastrointestinal cancer.