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Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects.

ABSTRACT: Circulating pancreatic glucagon is increased during fasting and maintains glucose balance by stimulating hepatic gluconeogenesis. Glucagon triggering of the cAMP pathway upregulates the gluconeogenic program through the phosphorylation of cAMP response element-binding protein (CREB) and the dephosphorylation of the CREB coactivator CRTC2. Hormonal and nutrient signals are also thought to modulate gluconeogenic gene expression by promoting epigenetic changes that facilitate assembly of the transcriptional machinery. However, the nature of these modifications is unclear. Using mouse models and in vitro assays, we show that histone H3 acetylation at Lys 9 (H3K9Ac) was elevated over gluconeogenic genes and contributed to increased hepatic glucose production during fasting and in diabetes. Dephosphorylation of CRTC2 promoted increased H3K9Ac through recruitment of the lysine acetyltransferase 2B (KAT2B) and WD repeat-containing protein 5 (WDR5), a core subunit of histone methyltransferase (HMT) complexes. KAT2B and WDR5 stimulated the gluconeogenic program through a self-reinforcing cycle, whereby increases in H3K9Ac further potentiated CRTC2 occupancy at CREB binding sites. Depletion of KAT2B or WDR5 decreased gluconeogenic gene expression, consequently breaking the cycle. Administration of a small-molecule KAT2B antagonist lowered circulating blood glucose concentrations in insulin resistance, suggesting that this enzyme may be a useful target for diabetes treatment.

SUBMITTER: Ravnskjaer K

PROVIDER: S-EPMC3784539 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects.

Ravnskjaer Kim K Hogan Meghan F MF Lackey Denise D Tora Laszlo L Dent Sharon Y R SY Olefsky Jerrold J Montminy Marc M

The Journal of clinical investigation 20130924 10

Circulating pancreatic glucagon is increased during fasting and maintains glucose balance by stimulating hepatic gluconeogenesis. Glucagon triggering of the cAMP pathway upregulates the gluconeogenic program through the phosphorylation of cAMP response element-binding protein (CREB) and the dephosphorylation of the CREB coactivator CRTC2. Hormonal and nutrient signals are also thought to modulate gluconeogenic gene expression by promoting epigenetic changes that facilitate assembly of the transc ...[more]

PMID: 24051374

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Project description:During fasting, increases in circulating pancreatic glucagon maintain glucose balance by up-regulating hepatic gluconeogenesis. Triggering of the cAMP pathway stimulates the gluconeogenic program through the phosphorylation of CREB and via the de-phosphorylation of the CREB coactivator CRTC2. Hormonal and nutrient signals are also thought to modulate gluconeogenic genes by promoting epigenetic changes that facilitate assembly of the transcriptional machinery, although the nature of these modifications is unclear. Here we show that histone H3 acetylation at Lys 9 (H3K9Ac) is elevated over gluconeogenic genes during fasting and in diabetes, where it contributes to increases in hepatic glucose production. Following its dephosphorylation, CRTC2 promoted increases in H3K9Ac by mediating the recruitment of the lysine acetyltransferase 2B (KAT2B) and WD repeat-containing protein 5 (WDR5), a core subunit of histone methyltransferase (HMT) complexes. In turn, KAT2B and WDR5 stimulated the gluconeogenic program through a self-reinforcing cycle whereby increases in H3K9Ac further potentiated CRTC2 occupancy at CREB binding sites. Breaking this cycle, by depletion of KAT2B or WDR5, decreased gluconeogenic gene expression. As administration of a small molecule KAT2B antagonist lowered circulating blood glucose concentrations in insulin resistance, our results demonstrate how this enzyme may be a useful target for diabetes treatment. A subset of cAMP responsive genes depend on specific recruitment of KAT2B (pcaf), which in concert with WDR5 acetylates H3K9. By selectively depleting hepatocytes for KAT2B or WDR5 prior to glucagon stimulation we explore, which genes rely on KAT2B and WDR5 activity. mKAT2B or mWDR5 were knocked down in primary mouse hepatocytes using adenoviral transduction with appropriate shRNAs. Control cells were transduced with a non-specific (NS) shRNA. 72 hours post transduction some cells were stimulated for 90 minutes with 100nM glucagon and others with PBS. Total RNA was purified and subjected to micro-RNA analysis. All samples are pools of RNA from three sepearate dishes. One replicate is included for most samples.

Dataset Information

Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects.

Publications

Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects.

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