CRL4DCAF8Ubiquitin 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 CRL4DCAF8expression 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.
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Gaofeng
G
Li
Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Tong
T
Ji
Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Jiang
J
Chen
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China; Zhejiang Key Laboratory of Gastro-Intestinal Pathophysiology, Zhejiang Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310058, China.
Yufei
Y
Fu
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Lidan
L
Hou
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Yan
Y
Feng
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Tingyue
T
Zhang
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Tianyu
T
Song
Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Jie
J
Zhao
Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92121, USA.
Yoko
Y
Endo
Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Hui
H
Lin
Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: cxjzu@hotmail.com.
Xiujun
X
Cai
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: cangyong@zju.edu.cn.
Yong
Y
Cang
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D044127:Epigenesis, Genetic; D020868:Gene Silencing / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
D006657:Histones; D025801:Ubiquitin; D011495:Histone-Lysine N-Methyltransferase; D044767:Ubiquitin-Protein Ligases
AFP; CRL4; DCAF8; DDB1; GPC3; H19; H3 ubiquitination; H3K9 methylation; liver maturation