Negative Elongation Factor Controls Energy Homeostasis in Cardiomyocytes

Abstract

SUMMARYNegative 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.

Dynamic change of transcription pausing through modulating NELF protein stability regulates granulocytic differentiation

“…Studies of transcription profiles in NELF-depleted cells revealed more down-regulated genes than up-regulated genes, suggesting a positive role of NELF in maintaining gene expression 11 . This was further supported by studies showing that NELF depletion causes either nucleosome reassembly on promoters or less recruitment of transcription initiation factors 11–14 , suggesting a role of paused Pol II in maintaining gene expression by facilitating initiation and generating a permissive chromatin state around the promoter region.…”

The role of ZKSCAN3 in the transcriptional regulation of autophagy

“…The procedures for mRNA expression were as described previously. 14 The primers used are listed in Table 1. The expression of individual genes was normalized to the expression of the ribosomal gene Rps21.…”

RNA polymerase II pausing as a context-dependent reader of the genome

“…Accordingly, NELF knockouts are embryonic lethal and its conditional knockouts lead to spontaneous death of mice (Amleh et al 2009). However, recent work demonstrated that mouse embryonic fibroblasts (Sun et al 2011), cardiomyocytes (Pan et al 2014), blastocysts (Amleh et al 2009) or embryonic stem cells (Williams et al 2015) can survive at least for several days in culture without a functional NELF-B gene, indicating that transcription can take place without NELF, or at least with greatly diminished amounts of residual NELF (Sun et al 2011; Williams et al 2015). Importantly, knockout of NELF-B resulted in failure of mouse embryonic stem cells to differentiate in vitro , suggesting that the NELF complex – and by extension Pol II pausing – is required for proper cell differentiation (Williams et al 2015).…”