Genomics

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BRD4 links carbohydrate and lipid synthetic pathways to a core transcriptional network for a cell-type specific metabolic response (ChIP-Seq 3T3-L1)


ABSTRACT: Glucose and fat metabolism are tightly interconnected where endogenous de novo lipogenesis (DNL) serves to convert carbohydrates directly into lipids. Here, we explored the role of the long isoform Brd4 as a key transcriptional co-activator in lipogenesis. As a member of the Bromo-extraterminal (BET) protein family, Brd4 is characterized by two tandem bromodomains that bind acetylated lysine on both histone and non-histone proteins in chromatin. We found that treatment with MS417, a small molecule inhibitor of Brd4 binding to acetylated lysine, suppresses 3T3-L1 adipocyte differentiation. MS417-treated obese (ob/ob) mice displayed resistance to weight gain and loss of fat from steatotic livers. Comprehensive RNA-seq and ChIP-seq analyses delineate a Brd4-driven gene network required for glycolysis-lipogenesis flux that is shared between glycolytic liver and 3T3-L1 adipocytes, but absent in the non-glycolytic white abdominal fat. Our data further reveal that Brd4 functions to provide specific metabolic resources, such as acetyl-CoA and nicotinamide adenine dinucleotide (NAD) cofactors, in cell types utilizing DNL. Collectively, these findings provide a novel view of the critical role Brd4 plays in orchestrating transcription of a network of genes directing metabolic pathways governing carbohydrate fueled lipid metabolism fundamental for controlling glucose homeostasis and body weight.

ORGANISM(S): Mus musculus

PROVIDER: GSE59158 | GEO | 2018/03/31

REPOSITORIES: GEO

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