CRL4^DCAF8 Ubiauitin Ligase Targets Histone H3K79 And Promotes H3K9 Methvlation In The Liver

Transcription from chromosomes is regulated by posttranslational modifications to histones such as methylation and ubiquitination.Monoubiquitination of histones H2A and H2B influences H3 methylation to reinforce the activation or repression of gene expression.Here we provide evidence that H3 polyubiquitination represses transcription of fetal and cell cycle genes in postnatal mouse liver,by crosstalk with H3K9 methylation.We found that the CRL4(DDB1-Cul4-Rbxl)ubiquitin ligase targets histone H3 for polyubiquitination at K79 via the substrate receptor DCAF8 in hepatocytes.Genetic inactivation of DCAF8,overexpression of an H3K79 mutant in liver cells or inducible deletion of DDB1 in mouse liver abrogates H3 ubiquitination,re-activates the expression of fetal liver and cell cycle genes by interfering with methylated H3K9 occupancy,and leads to cell senescence.Decreased H3 ubiquitination is also found in human liver cancer cell lines,and restoring CRL4DCAF reinstates the epigenetic gene silencing.Our results suggest that H3 ubiquitination coordinates the gene silencing program during postnatal liver maturation and its dysregulation may contribute to liver diseases such as cancer.