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.