CRL4DCAF8 Ubiquitin Ligase Targets Histone H3K79 and Promotes H3K9 Methylation in the Liver

Abstract

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 CRL4 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.

DCAF8, a novel MuRF1 interaction partner, promotes muscle atrophy

“…We also detected DCAF8-FLAG in precipitates of DDB1-HA and retrieved DDB1-FLAG upon purification of DCAF8-Myc(His) 6 ( Fig. 4B,C), which is in agreement with published data (Li et al, 2017). Interestingly, we and/or DCAF8-FLAG were transfected into COS-7 cells and the stability of these proteins was determined in cycloheximide (CHX) decay assays followed by immunoblotting using the indicated antibodies.…”

“…DCAF8 has been proposed to serve as substrate receptor in CRL4 complexes in non-muscle cells (Jin et al, 2006;Li et al, 2017). Such modular E3 ligases usually contain a Cul4A or Cul4B cullin scaffolding protein, which recruits the RING-finger protein RBX1 or RBX2, the adaptor protein DDB1, and different DCAF proteins involved in substrate binding (Angers et al, 2006).…”

“…MuRF1 and DCAF8 link CRL4 ligase complexes to muscle atrophy DCAF proteins typically constitute substrate receptors for CRL4 ubiquitin ligase complexes. Indeed, a DCAF8-containing CRL4A complex was recently shown to ubiquitylate histone H3 in nonmuscle cells, which is important for postnatal liver maturation (Li et al, 2017). Notably, CRL4A-DCAF8 complexes seem to be important factors for the development and/or homeostasis of neuronal cells.…”

Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex

“…Mediates degradation of stem-loop binding protein [84], histone mRNA maturation [84,85] DCAF8 WDR42A Targets histone H3K79 for polyubiquitination [86], p.R317C mutation results in decreased DDB1-DCAF8 association [87] Cereblon CRBN Degradation of MEIS2 [88], functions as Lon-type protease in mitochondria [89] PAFAH1B1 LIS1…”

The Molecular Chaperone Heat Shock Protein 70 Controls Liver Cancer Initiation and Progression by Regulating Adaptive DNA Damage and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling Pathways

“…Furthermore, beyond the potential link between epigenetic markers and senescence, the dramatic induced expression, especially of H3K9me modification, in the livers of mutant mice at 5 months post-DEN treatment suggests another interesting mechanism for tumor inhibition at the level of HCC progenitors. Indeed, methylation of H3K9me has been shown to progressively silence the fetal liver gene signature during liver maturation (e.g., AFP, insulin-like growth factor 2 [IGF2], GPC3, and H19), and this repressive function is likely to have a negative impact on the development of liver cancer progenitors and malignant cell transformation (97). The profile of expression of HP1␥, which has a role in transcription repression and propagation of heterochromatin structure (98), did not differ between the genotypes.…”