机构地区:[1]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 [2]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 [3]Department of Clinical Laboratory,The First People's Hospital of Lianyungang,The Affiliated Lianyungang Hospital of Xuzhou Medical University,Lianyungang 222000,China [4]Sylvester Comprehensive Cancer Center and Department of Medicine,University of Miami Miller School of Medicine,Miami,FL 33136,USA [5]Department of Biomedical Science,Schmidt College of Medicine,Florida Atlantic University,Boca Raton,FL 33431,USA
出 处:《Frontiers of Medicine》2024年第5期831-849,共19页医学前沿(英文版)
基 金:supported by the Center for High Performance Computing at Shanghai Jiao Tong University;supported by the National Key R&D Plan of China(No.2018YFA0107802 to Xiaojian Sun,Nos.2018YFA0107200 and 2018YFA0800203 to Lan Wang);the National Natural Science Foundation of China General Program(Nos.81970150 and 82170156 to Lan Wang);Shanghai“Science and Technology Innovation Action Plan”Excellent Academic/Technical Leader Program(Youth)(No.21XD1424500 to Lan Wang);Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01 to Saijuan Chen and Xiaojian Sun);Samuel Waxman Cancer Research Foundation,and the Shanghai Guangci Translational Medical Research Development Foundation.
摘 要: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 patientderived catalytically dead Setd2(Setd2-CD).We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity,as the Setd2 CD/CD and Setd2^(−/−)mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns.However,compared with Setd2^(−/−),the Setd2 CD/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.
关 键 词:Setd2 H3K36 methylation EPIGENETICS embryonic development cancer
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