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

Abstract

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 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.

Keywords

Setd2 / H3K36 methylation / epigenetics / embryonic development / cancer

Shubei Chen et al

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Acknowledgements

The computations in this study were run on the Siyuan-1 cluster supported by the Center for High Performance Computing at Shanghai Jiao Tong University. This work was 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.

Compliance with ethics guidelines

Conflicts of interest 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, Zhu Chen, Lan Wang, and Xiaojian Sun declare no potential conflicts of interest. Saijuan Chen is one of Editors-in-Chief of Frontiers of Medicine, who was excluded from the peer-review process and all editorial decisions related to the acceptance and publication of this article. Peer-review was handled independently by the other editors to minimise bias.

All the procedure of this study was approved by the Institutional Review Board of the Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The animal studies were approved by the Committee of Animal Use at Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences. All institutional and national guidelines for the care and use of laboratory animals were followed.

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