Genomic Coordination of Hepatic Lipid Metabolism and Fasting by BCL6

Sommars, Meredith Anne

doi:https://doi.org/10.21985/n2-639e-5s71

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Genomic Coordination of Hepatic Lipid Metabolism and Fasting by BCL6

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Transcription is tightly regulated to ensure genes are appropriately expressed both temporally and spatially. This tight regulation governs various processes within the cell, such as differentiation and cell identity, cellular maintenance, and dynamic responses to external signals. Transcription factors (TFs) coordinate these various gene programs and in particular, are key to enabling cells to dynamically adjust gene expression programs in response to intracellular and environmental signals. For example, transcription is tightly coordinated to maintain energy homeostasis during periods of feeding or fasting, but the TFs that control these alternating gene programs are incompletely understood. Many activators of transcription have been well characterized in regulating this metabolic shift, but the role of repressors in directing related metabolic gene expression changes is particularly uncharacterized. Here, we find that the B cell lymphoma 6 (BCL6) repressor is enriched in the fed state and converges genome-wide with PPAR to potently suppress the induction of fasting transcription. Deletion of hepatocyte Bcl6 in mice (Bcl6LKO) enhances lipid catabolism and ameliorates high fat diet-induced steatosis. In Ppara-null mice, hepatocyte Bcl6 ablation restores enhancer activity at PPAR-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.

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