首页|Catalytic activity of Setd2 is essential for embryonic development in mice:establishment of a mouse model harboring patient-derived Setd2 mutation

Catalytic activity of Setd2 is essential for embryonic development in mice:establishment of a mouse model harboring patient-derived Setd2 mutation

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Catalytic activity of Setd2 is essential for embryonic development in mice:establishment of a mouse model harboring patient-derived Setd2 mutation
SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation(H3K36me3).Mutations in SETD2 cause human diseases including cancer and developmental defects.In mice,Setd2 is essential for embryonic vascular remodeling.Given that many epigenetic modifiers have recently been found to possess noncatalytic functions,it is unknown whether the major function(s)of Setd2 is dependent on its catalytic activity or not.Here,we established a site-specific knockin mouse model harboring a cancer patient-derived catalytically dead Setd2(Setd2-CD).We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity,as the Setd2CD/CD and Setd2-/-mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns.However,compared with Setd2-/-,the Setd2CD/CD mice showed less severe defects in allantois development,and single-cell RNA-seq analysis revealed differentially regulated allantois-specific 5'Hoxa cluster genes in these two models.Collectively,this study clarifies the importance of Setd2 catalytic activity in mouse development and provides a new model for comparative study of previously unrecognized Setd2 functions.

Setd2H3K36 methylationepigeneticsembryonic developmentcancer

Shubei Chen、Dianjia Liu、Bingyi Chen、Zijuan Li、Binhe Chang、Chunhui Xu、Ningzhe Li、Changzhou Feng、Xibo Hu、Weiying Wang、Yuanliang Zhang、Yinyin Xie、Qiuhua Huang、Yingcai Wang、Stephen D.Nimer、Saijuan Chen、Zhu Chen、Lan Wang、Xiaojian Sun

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Shanghai Institute of Hematology,State Key Laboratory of Omics and Diseases,National Research Center for Translational Medicine at Shanghai,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,and School of Life Sciences & Biotechnology,Shanghai Jiao Tong University Shanghai 200025,China

CAS Key Laboratory of Tissue Microenvironment and Tumor,Shanghai Institute of Nutrition and Health,Shanghai Institutes for Biological Sciences,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200031,China

Department of Clinical Laboratory,The First People's Hospital of Lianyungang,The Affiliated Lianyungang Hospital of Xuzhou Medical University,Lianyungang 222000,China

Sylvester Comprehensive Cancer Center and Department of Medicine University of Miami Miller School of Medicine,Miami,FL 33136 USA

Department of Biomedical Science,Schmidt College of Medicine,Florida Atlantic University,Boca Raton,FL 33431,USA

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Setd2 H3K36 methylation epigenetics embryonic development cancer

2024

10.1007/s11684-024-1095-1

医学前沿
高等教育出版社

医学前沿

CSTPCD
影响因子：1.362
ISSN：2095-0217
年,卷(期)：2024.18(5)