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

Gaofeng Li,Tong Ji,Jiang Chen,Yufei Fu,Lidan Hou,Yan Feng,Tingyue Zhang,Tianyu Song,Jie Zhao,Yoko Endo,Hui Lin,Xiujun Cai,Yong Cang

doi:10.1016/j.celrep.2017.01.039

Gaofeng Li, Tong Ji + Show 11 more

Open Access

PDF Available

https://doi.org/10.1016/j.celrep.2017.01.039

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

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 ofCRL4 in mouse liver abrogates H3 ubiquitination, reactivates the expression of fetal liver and cell-cyclegenes by interfering with methylated H3K9 occupancy, and leads to cell senescence. Restoring CRL4DCAF8 expression in cells with decreased H3ubiquitination reinstates the epigenetic gene silencing. Our results suggest that progressive H3 ubiquitination plays an important role in postnatal liver maturation.

Highlights

Posttranslational modifications of histones, including acetylation, phosphorylation, methylation, and ubiquitination, act alone, in concert, or by crosstalk to regulate many chromatin-mediated processes (Bannister and Kouzarides, 2011; Jenuwein and Allis, 2001; Suganuma and Workman, 2008)
Slow-migrating smears were robustly detected by a histone H3 antibody and a total ubiquitin antibody in chromatin fractionations prepared from adult mouse liver but only weakly in other mouse organs, including brain, kidney, spleen, and lung (Figure 1A)
Histone H3 was reported to be ubiquitinated by the CRL4 E3 ubiquitin ligase in response to DNA damage (Wang et al, 2006) or prior to be assembled to nucleosome in yeast and human cells (Han et al, 2013)

Summary

Introduction

Posttranslational modifications of histones, including acetylation, phosphorylation, methylation, and ubiquitination, act alone, in concert, or by crosstalk to regulate many chromatin-mediated processes (Bannister and Kouzarides, 2011; Jenuwein and Allis, 2001; Suganuma and Workman, 2008). Histone ubiquitination alters chromatin structures, recruits effector molecules, or causes histone turnover to control gene transcription and DNA repair (Braun and Madhani, 2012; Thorslund et al, 2015; Weake and Workman, 2008). The Cullin 4-RING ligase (CRL4) can add ubiquitin to H3 to facilitate the nucleotide excision repair (NER) of damaged DNA (Wang et al, 2006) or the transfer of H3-H4 dimers from histone chaperones to newly assembled nucleosomes (Han et al, 2013). By altering the function or stability of its substrates, CRL4 regulates cell-cycle progression, genome replication, and DNA damage repair

Results

Discussion

Conclusion