Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis

Meredith A. Sommars; Krithika Ramachandran; Madhavi D. Senagolage; Christopher R. Futtner; Derrik M. Germain; Amanda L. Allred; Yasuhiro Omura; Ilya R. Bederman; Grant D. Barish

doi:10.7554/eLife.43922

Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis

Meredith A. Sommars, Krithika Ramachandran, Madhavi D. Senagolage, Christopher R. Futtner, Derrik M. Germain, Amanda L. Allred, Yasuhiro Omura, Ilya R. Bederman, Grant D. Barish^*

^*Corresponding author for this work

Medicine, Endocrinology Division

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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 PPARa to potently suppress the induction of fasting transcription. Deletion of hepatocyte Bcl6 enhances lipid catabolism and ameliorates highfat- diet-induced steatosis. In Ppara-null mice, hepatocyte Bcl6 ablation restores enhancer activity at PPARa-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.

Original language	English (US)
Article number	e43922
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.43922
State	Published - Apr 2019

ASJC Scopus subject areas

Neuroscience(all)
Immunology and Microbiology(all)
Biochemistry, Genetics and Molecular Biology(all)

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title = "Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis",

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 PPARa to potently suppress the induction of fasting transcription. Deletion of hepatocyte Bcl6 enhances lipid catabolism and ameliorates highfat- diet-induced steatosis. In Ppara-null mice, hepatocyte Bcl6 ablation restores enhancer activity at PPARa-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.",

author = "Sommars, {Meredith A.} and Krithika Ramachandran and Senagolage, {Madhavi D.} and Futtner, {Christopher R.} and Germain, {Derrik M.} and Allred, {Amanda L.} and Yasuhiro Omura and Bederman, {Ilya R.} and Barish, {Grant D.}",

note = "Funding Information: We thank Joe Bass, Liming Pei, and Debabrata Chakravarti for helpful advice and discussion. We thank Northwestern University{\textquoteright}s Comprehensive Metabolic Core and Mouse Histology and Phenotyping Laboratory (supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center) for services. This work was funded by NIH grants R01DK108987 (GB) and K08HL092298 (GB), American Diabetes Association Award 1–17-IBS-137 (GB), and NIH T32 GM008061 (MS).",

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Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis. / Sommars, Meredith A.; Ramachandran, Krithika; Senagolage, Madhavi D.; Futtner, Christopher R.; Germain, Derrik M.; Allred, Amanda L.; Omura, Yasuhiro; Bederman, Ilya R.; Barish, Grant D.

In: eLife, Vol. 8, e43922, 04.2019.

Research output: Contribution to journal › Article › peer-review

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AU - Germain, Derrik M.

AU - Allred, Amanda L.

AU - Omura, Yasuhiro

AU - Bederman, Ilya R.

AU - Barish, Grant D.

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