Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions

H4K20 monomethylation maintains genome integrity by regulating proper mitotic condensation, DNA damage response, and replication licensing. Here, we show that, in non-dividing hepatic cells, H4K20Me1 is specifically enriched in active gene bodies and dynamically regulated by the antagonistic action...

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Published in:	Cell reports (Cambridge) Vol. 20; no. 4; pp. 909 - 922
Main Authors:	Nikolaou, Kostas C., Moulos, Panagiotis, Harokopos, Vangelis, Chalepakis, George, Talianidis, Iannis
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 25-07-2017 Cell Press Elsevier
Subjects:	Animals Gene Expression Regulation genome stability histone methylation Histones - genetics Histones - metabolism liver Liver - metabolism Male metabolism Mice Mice, Inbred C57BL Promoter Regions, Genetic - genetics Protein Methyltransferases - genetics Protein Methyltransferases - metabolism RNA Polymerase II - genetics RNA Polymerase II - metabolism transcription Transcription, Genetic - genetics histone methylation genome stability metabolism transcription liver
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Summary:	H4K20 monomethylation maintains genome integrity by regulating proper mitotic condensation, DNA damage response, and replication licensing. Here, we show that, in non-dividing hepatic cells, H4K20Me1 is specifically enriched in active gene bodies and dynamically regulated by the antagonistic action of Kmt5a methylase and Kdm7b demethylase. In liver-specific Kmt5a-deficient mice, reduced levels of H4K20Me1 correlated with reduced RNA Pol II release from promoter-proximal regions. Genes regulating glucose and fatty acid metabolism were most sensitive to impairment of RNA Pol II release. Downregulation of glycolytic genes resulted in an energy starvation condition partially compensated by AMP-activated protein kinase (AMPK) activation and increased mitochondrial activity. This metabolic reprogramming generated a highly sensitized state that, upon different metabolic stress conditions, quickly aggravated into a senescent phenotype due to ROS overproduction-mediated oxidative DNA damage. The results illustrate how defects in the general process of RNA Pol II transition into a productive elongation phase can trigger specific metabolic changes and genome instability. [Display omitted] •H4K20Me1 is dynamically deposited in the gene bodies of active genes•Kmt5a regulates RNA Pol II release from promoter-proximal pause sites•Kmt5a regulates metabolic gene transcription•The transcription regulatory function of Kmt5a is important for genome integrity Nikolaou et al. find that Kmt5a regulates the escape of RNA polymerase II from promoter-proximal pause sites and that this step is critical in the regulation of metabolic gene expression. The transcription regulatory function of Kmt5a is important for maintaining genome integrity in non-dividing cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2017.07.003