CRL4泛素连接酶靶向组蛋白H3K79并促进肝脏中的H3K9甲基化。
CRL4 Ubiquitin Ligase Targets Histone H3K79 and Promotes H3K9 Methylation in the Liver.
作者信息
Li Gaofeng, Ji Tong, Chen Jiang, Fu Yufei, Hou Lidan, Feng Yan, Zhang Tingyue, Song Tianyu, Zhao Jie, Endo Yoko, Lin Hui, Cai Xiujun, Cang Yong
机构信息
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
出版信息
Cell Rep. 2017 Feb 7;18(6):1499-1511. doi: 10.1016/j.celrep.2017.01.039.
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.
染色体转录受组蛋白翻译后修饰的调控，如甲基化和泛素化。组蛋白H2A和H2B的单泛素化影响H3甲基化，以加强基因表达的激活或抑制。在此，我们提供证据表明，H3多聚泛素化通过与H3K9甲基化的相互作用抑制出生后小鼠肝脏中胎儿和细胞周期基因的转录。我们发现，CRL4泛素连接酶通过肝细胞中的DCAF8底物受体靶向H3在K79处进行多聚泛素化。DCAF8的基因失活以及细胞中H3K79突变体的过表达或小鼠肝脏中CRL4的诱导性缺失消除了H3泛素化，通过干扰甲基化的H3K9占据重新激活胎儿肝脏和细胞周期基因的表达，并导致细胞衰老。在H3泛素化降低的细胞中恢复CRL4表达可恢复表观遗传基因沉默。我们的结果表明，渐进性H3泛素化在出生后肝脏成熟中起重要作用。
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