Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis
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 conve...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2019-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/43922 |
| _version_ | 1811201236276346880 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Meredith A Sommars |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:18:45Z |
| format | Article |
| id | doaj.art-31b0386732914031a75b86d14e851146 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:18:45Z |
| publishDate | 2019-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-31b0386732914031a75b86d14e8511462022-12-22T03:52:11ZengeLife Sciences Publications LtdeLife2050-084X2019-04-01810.7554/eLife.43922Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosisMeredith A Sommars0Krithika Ramachandran1Madhavi D Senagolage2Christopher R Futtner3Derrik M Germain4Amanda L Allred5Yasuhiro Omura6Ilya R Bederman7https://orcid.org/0000-0002-1909-5746Grant D Barish8https://orcid.org/0000-0001-8753-0546Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United StatesDivision of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United StatesDivision of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United StatesDivision of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United StatesDivision of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United StatesDivision of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United StatesDivision of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, United StatesDivision of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, United States; Jesse Brown VA Medical Center, Chicago, United StatesTranscription 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.https://elifesciences.org/articles/43922fastingsteatosisliverBCL6PPARrepressor |
| spellingShingle | 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 Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis eLife fasting steatosis liver BCL6 PPAR repressor |
| title | Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis |
| title_full | Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis |
| title_fullStr | Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis |
| title_full_unstemmed | Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis |
| title_short | Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis |
| title_sort | dynamic repression by bcl6 controls the genome wide liver response to fasting and steatosis |
| topic | fasting steatosis liver BCL6 PPAR repressor |
| url | https://elifesciences.org/articles/43922 |
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