Abstract
Transcription is tightly regulated to maintain energy homeostasis during periods of feeding or fasting, but the molecular factors that control these alternating gene programs are incompletely understood. Here, we find that the B cell lymphoma 6 (BCL6) repressor is enriched in the fed state and converges genome-wide with PPARα to potently suppress the induction of fasting transcription. Deletion of hepatocyte Bcl6 enhances lipid catabolism and ameliorates high-fat-diet-induced steatosis. In Ppara-null mice, hepatocyte Bcl6 ablation restores enhancer activity at PPARα-dependent genes and overcomes defective fasting-induced fatty acid oxidation and lipid accumulation. Together, these findings identify BCL6 as a negative regulator of oxidative metabolism and reveal that alternating recruitment of repressive and activating transcription factors to shared cis-regulatory regions dictates hepatic lipid handling.
Highlights
The classical studies of Jacob and Monod on the bacterial lac operon established a central paradigm for transcriptional repression to direct metabolic responses and sustain life in an environment of discontinuous food supply (Jacob and Monod, 1961; Payankaulam et al, 2010)
B cell lymphoma 6 (BCL6) colocalizes with peroxisome proliferator-activated receptor alpha (PPARa) at fasting-regulated genes controlling lipid oxidation
Since hepatocyte BCL6 binds to SMRT/NCoR-HDAC3 at a subset of its binding sites (Figure 3C and D), we examined HDAC3 occupancy at BCL6-PPARa peaks along rescued fasting genes
Summary
The classical studies of Jacob and Monod on the bacterial lac operon established a central paradigm for transcriptional repression to direct metabolic responses and sustain life in an environment of discontinuous food supply (Jacob and Monod, 1961; Payankaulam et al, 2010). Extended fasting further stimulates peroxisome proliferator-activated receptor alpha (PPARa) to induce fatty acid oxidation, ketogenesis, and the fasting hormone FGF21 (Badman et al, 2007; Inagaki et al, 2007; Kersten et al, 1999; Leone et al, 1999). Despite progress revealing these various transcriptional activators, their dynamic genome-wide regulation and the influence of additional factors, repressors, on the feeding to fasting transition remains poorly understood (Goldstein and Hager, 2015)
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