Abstract
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/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes.
Highlights
Hepatic glucose production is critical for the maintenance of normal blood levels to meet whole-body fuel requirements
We have discovered here that the demethylase Jhdm1a negatively regulates gluconeogenesis through suppressing the expression of two rate-limiting gluconeogenic enzymes
Gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to hyperglycemia
Summary
Hepatic glucose production is critical for the maintenance of normal blood levels to meet whole-body fuel requirements. Key DNA elements responsible for the hormonal regulation have been well characterized on the promoters of PEPCK and G6Pase gene [6,7,8,9] These elements serve as platforms for setting up a complex transcriptional machinery that includes transcription factors (e.g., CREB, FOXO1, FOXA2, C/EBPs, HNF4a, GR, Nur77) and cofactors (e.g., PGC-1a, CRTC2, SIRT1, p300/CBP, SRC-1), thereby driving gluconeogenic gene expression [10], [11]. Despite these tremendous progresses, the regulatory mechanisms upstream of this transcriptional network are incompletely understood. It is unclear how the chromatin landscape affects gluconeogenesis, what chromatin modifying enzymes (in addition to p300/CBP) are involved, and how these enzymes coordinate with the aforementioned transcriptional regulators
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