CRL4DCAF8 Ubiquitin Ligase Targets Histone H3K79 and Promotes H3K9 Methylation 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 ubiquitin ligase targets H3 for polyubiquitination at K79 via the DCAF8 substrate receptor in hepatocytes. Genetic inactivation of DCAF8 and overexpression of an H3K79 mutant in cells or inducible deletion of CRL4 in mouse liver abrogates H3 ubiquitination, reactivates the expression of fetal liver and cell-cycle genes by interfering with methylated H3K9 occupancy, and leads to cell senescence. Restoring CRL4DCAF8 expression in cells with decreased H3 ubiquitination reinstates the epigenetic gene silencing. Our results suggest that progressive H3 ubiquitination plays an important role in postnatal liver maturation. [Display omitted] •CRL4DCAF8 ubiquitinates histone H3 at K79•H3K79 is ubiquitinated during postnatal liver development•Loss of CRL4DCAF8 inhibits H3K9 methylation and activates fetal liver gene expression Expression of many fetal liver genes is progressively silenced during postnatal liver maturation. Li et al. report that CRL4DCAF8-ubiquitin-ligase-mediated polyubiquitination of histone H3K79 is activated in adult liver to promote H3K9 methylation and drive the silencing of fetal liver genes.