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Transcriptional and chromatin regulations mediate the liver response to nutrient availability. The role of chromatin factors involved in hormonal regulation in response to fasting is not fully understood. We have identified SETDB2, a glucocorticoid-induced putative epigenetic modifier, as a positive regulator of GR-mediated gene activation in liver. Insig2a increases during fasting to limit lipid synthesis, but the mechanism of induction is unknown. We show Insig2a induction is GR-SETDB2 dependent. SETDB2 facilitates GR chromatin enrichment and is key to glucocorticoid-dependent enhancer-promoter interactions. INSIG2 is a negative regulator of SREBP, and acute glucocorticoid treatment decreased active SREBP during refeeding or in livers of Ob/Ob mice, both systems of elevated SREBP-1c-driven lipogenesis. Knockdown of SETDB2 or INSIG2 reversed the inhibition of SREBP processing. Overall, these studies identify a GR-SETDB2 regulatory axis of hepatic transcriptional reprogramming and identify SETDB2 as a potential target for metabolic disorders with aberrant glucocorticoid actions.

Original publication

DOI

10.1016/j.cmet.2016.07.025

Type

Journal article

Journal

Cell metabolism

Publication Date

09/2016

Volume

24

Pages

474 - 484

Addresses

Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA.

Keywords

Liver, Chromatin, Animals, Mice, Inbred C57BL, Mice, Obese, Dexamethasone, Histone-Lysine N-Methyltransferase, Lysine, Membrane Proteins, Histones, Receptors, Glucocorticoid, RNA, Messenger, Glucocorticoids, Feeding Behavior, Transcription, Genetic, Gene Expression Regulation, Protein Binding, Methylation, Male, Lipid Metabolism, Sterol Regulatory Element Binding Protein 1, Enhancer Elements, Genetic, Promoter Regions, Genetic, Gene Knockdown Techniques, Genetic Loci