Negative Elongation Factor Controls Energy Homeostasis in Cardiomyocytes
Haihui Pan,
Kunhua Qin,
Zhanyong Guo,
Yonggang Ma,
Craig April,
Xiaoli Gao,
Thomas G. Andrews,
Alex Bokov,
Jianhua Zhang,
Yidong Chen,
Susan T. Weintraub,
Jian-Bing Fan,
Degeng Wang,
Yanfen Hu,
Gregory J. Aune,
Merry L. Lindsey,
Rong Li
Affiliations
Haihui Pan
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Kunhua Qin
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Zhanyong Guo
Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Yonggang Ma
Department of Medicine, San Antonio Cardiovascular Proteomics Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Craig April
Illumina, Inc., San Diego, CA 92121, USA
Xiaoli Gao
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Thomas G. Andrews
Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Alex Bokov
Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Jianhua Zhang
Department of Medicine, San Antonio Cardiovascular Proteomics Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Yidong Chen
Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Susan T. Weintraub
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Jian-Bing Fan
Illumina, Inc., San Diego, CA 92121, USA
Degeng Wang
Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Yanfen Hu
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Gregory J. Aune
Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Merry L. Lindsey
Department of Medicine, San Antonio Cardiovascular Proteomics Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Rong Li
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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.
