title: SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation.
abstract: 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.
authors: Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors: Manuel
authors: M
authors: Roqueta-Rivera
authors: Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors: Ryan M
authors: RM
authors: Esquejo
authors: Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors: Peter E
authors: PE
authors: Phelan
authors: Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors: Katalin
authors: K
authors: Sandor
authors: Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors: Bence
authors: B
authors: Daniel
authors: INSERM, UMR-S 872, Centre de Recherches des Cordeliers, 75006 Paris, France; Université Pierre et Marie Curie-Paris, 75005 Paris, France.
authors: Fabienne
authors: F
authors: Foufelle
authors: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, FL 32827, USA.
authors: Jun
authors: J
authors: Ding
authors: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, FL 32827, USA.
authors: Xiaoman
authors: X
authors: Li
authors: Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors: Sepideh
authors: S
authors: Khorasanizadeh
authors: Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA. Electronic address: tosborne@sbpdiscovery.org.
authors: Timothy F
authors: TF
authors: Osborne
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005247:Feeding Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056426:Genetic Loci; D005938:Glucocorticoids / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002843:Chromatin; D005938:Glucocorticoids; D006657:Histones; C506120:Insig2 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D051780:Sterol Regulatory Element Binding Protein 1; D003907:Dexamethasone; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine
keywords: SETDB2; SREBP; fasting liver; glucocorticoid receptor; insig2