GSE97338
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 the gene bodies of active genes and dynamically regulated by the antagonistic action of PR-Set7 methylase and Phf8 demethylase. In liver-specific PR-Set7-deficient mice, reduced H4K20Me1 levels primarily affected RNAPII release from promoter-proximal regions. Glucose and fatty acid metabolic genes were highly sensitive to impaired RNAPII release. Downregulation of glycolytic genes resulted in an energy starvation condition partially compensated by AMPK activation and increased mitochondrial activity. This metabolic reprogramming generated a normoglycemic, but highly sensitized state, which upon different metabolic stress conditions, quickly aggravated into a senescent phenotype initiated by ROS overproduction and oxidative DNA damage. The results illustrate how defects in the general process of RNAPII transition into elongation phase can trigger specific metabolic changes, which lead to genome instability. Overall design: PR-Set7 (other name Set8; Setd8) knockout mice (other name Set8; Setd8) were generated by crossing PR-SET7loxp mice carrying floxed exon 7 allele of PR-SET7 (Oda et al., 2009) with Alb-Cre mice (Yakar et al., 1999) in mixed F1 background. Mice (WT = Wild type; Set8-KO = Setd8-KO; PR-SET7-KO) were sacrificed at 45 days postnatal age. Livers from these mice were used for ChIP-seq and RNA-seq approaches. For Global Run-On sequencing newly synthesized RNA GRO-EU-seq, mice were treated with xxx mg /g bodyweight Ethydyl-Uridine (EU) before sacrifice. For the GRO-Br-seq experiments nuclei were prepared from the livers and treated with Br-UTP for 3 minutes.