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Cell Rep. 2014 Apr 10;7(1):79-85. doi: 10.1016/j.celrep.2014.02.028. Epub 2014 Mar 20.

Negative elongation factor controls energy homeostasis in cardiomyocytes.

Author information

1
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
2
Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
3
Department of Medicine, San Antonio Cardiovascular Proteomics Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
4
Illumina, Inc., San Diego, CA 92121, USA.
5
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
6
Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
7
Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
8
Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
9
Department of Medicine, San Antonio Cardiovascular Proteomics Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic address: mllindsey@umc.edu.
10
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic address: lir3@uthscsa.edu.

Abstract

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 α (PPARα), 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 PPARα-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes.

PMID:
24656816
PMCID:
PMC4277258
DOI:
10.1016/j.celrep.2014.02.028
[Indexed for MEDLINE]
Free PMC Article
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