Journal
CELL REPORTS
Volume 7, Issue 1, Pages 79-85Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.02.028
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Funding
- DOD [BC100388]
- NIH/NLM [R01LM010212]
- NIH/NHLBI HHSN [268201000036C (N01-HV-00244), HL051971, R01 HL075360]
- VA [5I01BX000505]
- NIH/NCRR [1S10OD016417-01]
- NCATS [8UL1TR000149]
- San Antonio Nathan Shock Center
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Negative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here, we show that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress. Tissue-specific knockout of NELF-B confirms its cell-autonomous function in cardiomyocytes. NELF directly supports transcription of those genes encoding rate-limiting enzymes in fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle. NELF also shares extensively transcriptional target genes with peroxisome proliferator-activated receptor alpha (PPAR alpha), a master regulator of energy metabolism in the myocardium. Mechanistically, NELF helps stabilize the transcription initiation complex at the metabolism-related genes. Our findings strongly indicate that NELF is part of the PPAR alpha-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes.
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