Cell Reports: Negative Elongation Factor Controls Energy Homeostasis in Cardiomyocytes

HaihuiPan1 KunhuaQin1 ZhanyongGuo23 YonggangMa4CraigApril7 XiaoliGao5T homas G.Andrews2 AlexBokov3 JianhuaZhang4 YidongChen23 Susan T.Weintraub5 Jian-BingFan7 DegengWang 23YanfenHu1 Gregory J.Aune26 Merry L.Lindsey4 RongLi1

Summary

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.

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