Program in Gene Function and Expression; Program in Molecular Medicine; Department of Molecular Genetics and Microbiology; Department of Medicine, Division of Cardiovascular Medicine
Jumonji Domain-Containing Histone Demethylases; Gluconeogenesis
Genetics and Genomics
Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPalpha. This is achieved, at least in part, by its USF1-dependent association with the C/EBPalpha promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPalpha locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes.
Rights and Permissions
Copyright: © 2012 Pan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Pan D, Mao C, Zou T, Yao AY, Cooper MP, et al. (2012) The Histone Demethylase Jhdm1a Regulates Hepatic Gluconeogenesis. PLoS Genet 8(6): e1002761. doi:10.1371/journal.pgen.1002761 Link to article on publisher's site
Pan D, Mao C, Zou T, Yao AY, Cooper MP, Boyartchuk VL, Wang Y. (2012). The histone demethylase jhdm1a regulates hepatic gluconeogenesis. Program in Gene Function and Expression Publications. https://doi.org/10.1371/journal.pgen.1002761. Retrieved from https://escholarship.umassmed.edu/pgfe_pp/195