DNA methylation in AgRP neurons regulates voluntary exercise behavior in mice

Harry MacKay, C. Anthony Scott, Jack D. Duryea, Maria S. Baker, Eleonora Laritsky, Amanda E. Elson, Theodore Garland, Marta L. Fiorotto, Rui Chen, Yumei Li, Cristian Coarfa, Richard B. Simerly and Robert A. Waterland ()
Additional contact information
Harry MacKay: USDA/ARS Children’s Nutrition Research Center
C. Anthony Scott: USDA/ARS Children’s Nutrition Research Center
Jack D. Duryea: USDA/ARS Children’s Nutrition Research Center
Maria S. Baker: USDA/ARS Children’s Nutrition Research Center
Eleonora Laritsky: USDA/ARS Children’s Nutrition Research Center
Amanda E. Elson: Vanderbilt University
Theodore Garland: University of California
Marta L. Fiorotto: USDA/ARS Children’s Nutrition Research Center
Rui Chen: Baylor College of Medicine
Yumei Li: Baylor College of Medicine
Cristian Coarfa: Baylor College of Medicine
Richard B. Simerly: Vanderbilt University
Robert A. Waterland: USDA/ARS Children’s Nutrition Research Center

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract DNA methylation regulates cell type-specific gene expression. Here, in a transgenic mouse model, we show that deletion of the gene encoding DNA methyltransferase Dnmt3a in hypothalamic AgRP neurons causes a sedentary phenotype characterized by reduced voluntary exercise and increased adiposity. Whole-genome bisulfite sequencing (WGBS) and transcriptional profiling in neuronal nuclei from the arcuate nucleus of the hypothalamus (ARH) reveal differentially methylated genomic regions and reduced expression of AgRP neuron-associated genes in knockout mice. We use read-level analysis of WGBS data to infer putative ARH neural cell types affected by the knockout, and to localize promoter hypomethylation and increased expression of the growth factor Bmp7 to AgRP neurons, suggesting a role for aberrant TGF-β signaling in the development of this phenotype. Together, these data demonstrate that DNA methylation in AgRP neurons is required for their normal epigenetic development and neuron-specific gene expression profiles, and regulates voluntary exercise behavior.

Date: 2019
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DOI: 10.1038/s41467-019-13339-3

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