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Genomic and epigenomic mapping of leptin-responsive neuronal populations involved in body weight regulation

By Fumitaka Inoue, Walter L Eckalbar, Yi Wang, Karl K Murphy, Navneet Matharu, Christian Vaisse, Nadav Ahituv

Posted 07 Apr 2019
bioRxiv DOI: 10.1101/601070 (published DOI: 10.1038/s42255-019-0051-x)

Genome wide association studies (GWAS) in obesity have identified a large number of noncoding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, few obesity-associated SNPs have been functionally characterized. Leptin responsive neurons in the hypothalamus are essential in controlling energy homeostasis and body weight. Here, we combine FACS-sorting of leptin-responsive hypothalamic neuron nuclei with genomic and epigenomic approaches (RNA-seq, ChIP-seq, ATAC-seq) to generate a comprehensive map of leptin-response specific regulatory elements, several of which overlap obesity-associated GWAS variants. We demonstrate the usefulness of our leptin-response neuron regulome, by functionally characterizing a novel enhancer near Socs3, a leptin response-associated transcription factor. We envision our data to serve as a useful resource and a blueprint for functionally characterizing obesity-associated SNPs in the hypothalamus.

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