Temporal Integrative Omics Reveals an Increase in Nondegradative Ubiquitylation during Primary Hepatocyte Dedifferentiation  

作　　者：Zhengyi Jiang Zeyu Sun Xiaoxi Ouyang Yalei Zhao Menghao Zhou Baohong Wang Qirui Li Linxiao Fan Sainan Zhang Lanjuan Li 

机构地区：[1]State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,National Clinical Research Center for Infectious Diseases,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,The First Affiliated Hospital,College of Medicine,Zhejiang University,Hangzhou 310003,China

出　　处：《Engineering》2020年第11期1302-1314,共13页工程（英文）

基　　金：This work was supported by the National Key Research and Development Program of China(2016YFC1101304/3);the National Natural Science Foundation of China(81400589,81790630,and 81790633);Research Unit of Infectious Diseases and Microecology,Chinese Academy of Medical Sciences(2019RU021).

摘　　要：Primary hepatocytes(PHCs)are widely used in various fields,but the progressive deterioration of liverspecific features in vitro significantly limits their application.While the transcriptional regulation and whole cell proteome(WCP)of PHCs have been extensively studied,only a small number of studies have addressed the role of posttranslational modifications in this process.To elucidate the underlying mechanisms that induce dedifferentiation,we carried out parallel quantifications of the transcriptome,WCP,ubiquitinome,and phosphoproteome of rat PHCs after 0,6,12,24,and 48 h of in vitro culture.Our data constitute a detailed proteomic analysis of dedifferentiated PHCs including 2196 proteins,2056 ubiquitinated sites,and 4932 phosphorylated peptides.We revealed a low correlation between the transcriptome and WCP during dedifferentiation.A combined analysis of the ubiquitinome with the corresponding WCP indicated that the dedifferentiation of PHCs led to an increase in nondegradative K27 ubiquitination.Functional analysis of the altered phosphoproteins suggested a significant enrichment in ferroptosis.In all,404 proteins with both ubiquitination and phosphorylation were identified to be involved in critical metabolic events.Furthermore,Ptbph Hnqjd,Hnrnpu,and Srrm2 were identified as hub genes.Taken together,our data provide new insights into proteome dynamics during PHC dedifferentiation and potential targets to inhibit the dedifferentiation process.

关 键 词：UBIQUITINATION PHOSPHOPROTEOME PROTEOME DEDIFFERENTIATION Primary hepatocytes 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]