|Li, Ge - Children'S Nutrition Research Center (CNRC)|
|Zhang, Wenjuan - Children'S Nutrition Research Center (CNRC)|
|Baker, Maria - Children'S Nutrition Research Center (CNRC)|
|Laritsky, Eleonora - Children'S Nutrition Research Center (CNRC)|
|Mattan-hung, Natalia - Children'S Hospital Los Angeles|
|Yu, Dahai - Children'S Nutrition Research Center (CNRC)|
|Kunde-ramamoorthy, Govindarajan - Children'S Nutrition Research Center (CNRC)|
|Simerly, Richard - Children'S Hospital Los Angeles|
|Chen, Rui - Children'S Nutrition Research Center (CNRC)|
|Shen, Lanlan - Children'S Nutrition Research Center (CNRC)|
|Waterland, Robert - Children'S Nutrition Research Center (CNRC)|
Submitted to: Human Molecular Genetics
Publication Type: Review Article
Publication Acceptance Date: 10/28/2013
Publication Date: 11/1/2013
Citation: Li, G., Zhang, W., Baker, M.S., Laritsky, E., Mattan-Hung, N., Yu, D., Kunde-Ramamoorthy, G., Simerly, R.B., Chen, R., Shen, L., Waterland, R.A. 2013. Major epigenetic development distinguishing neuronal and non-neuronal cells occurs postnatally in the murine hypothalamus. Human Molecular Genetics. 23 (6):1579-1590.
Interpretive Summary: The hypothalamus is the central nervous system's 'control center' for the integrated regulation of food intake and energy expenditure, and therefore plays a critical role in energy balance and obesity. To identify potential critical developmental periods for epigenetic development in the hypothalamus, we studied DNA methylation changes in the hypothalamus from birth to weaning in mice. Because different cell types have different DNA methylation patterns, we separated the two major brain cell types – neurons and glia – and performed genome-scale DNA methylation profiling in both. Our results show that the suckling period is a critical period for epigenetic development in the hypothalamus, with major changes in DNA methylation occurring principally in neurons. Additional studies are necessary to more fully understand the impact of the suckling period on energy balance.
Technical Abstract: Prenatal and early postnatal environment can persistently alter one's risk of obesity. Environmental effects on hypothalamic developmental epigenetics constitute a likely mechanism underlying such 'developmental programming' of energy balance regulation. To advance our understanding of these processes, it is essential to develop approaches to disentangle the cellular and regional heterogeneity of hypothalamic developmental epigenetics. We therefore performed genome-scale DNA methylation profiling in hypothalamic neurons and non-neuronal cells at postnatal day 0 (P0) and P21 and found, surprisingly, that most of the DNA methylation differences distinguishing these two cell types are established postnatally. In particular, neuron-specific increases in DNA methylation occurred extensively at genes involved in neuronal development. Quantitative bisulfite pyrosequencing verified our methylation profiling results in all 15 regions examined, and expression differences were associated with DNA methylation at several genes. We also identified extensive methylation differences between the arcuate (ARH) and paraventricular nucleus of the hypothalamus (PVH). Integrating these two data sets showed that genomic regions with PVH versus ARH differential methylation strongly overlap with those undergoing neuron-specific increases from P0 to P21, suggesting that these developmental changes occur preferentially in either the ARH or PVH. In particular, neuron-specific methylation increases at the 3' end of Shh localized to the ARH and were positively associated with gene expression. Our data indicate a key role for DNA methylation in establishing the gene expression potential of diverse hypothalamic cell types, and provide the novel insight that early postnatal life is a critical period for cell type-specific epigenetic development in the murine hypothalamus.