. 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
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.
Y Aubert, S Egolf, BC Capell. The unexpected noncatalytic roles of histone modifiers in development and disease. Trends Genet 2019; 35(9): 645–657 https://doi.org/10.1016/j.tig.2019.06.004
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MAJ Morgan, A Shilatifard. Reevaluating the roles of histone-modifying enzymes and their associated chromatin modifications in transcriptional regulation. Nat Genet 2020; 52(12): 1271–1281 https://doi.org/10.1038/s41588-020-00736-4
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MAJ Morgan, A Shilatifard. Epigenetic moonlighting: catalytic-independent functions of histone modifiers in regulating transcription. Sci Adv 2023; 9(16): eadg6593 https://doi.org/10.1126/sciadv.adg6593
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KO Kizer, HP Phatnani, Y Shibata, H Hall, AL Greenleaf, BD Strahl. A novel domain in Set2 mediates RNA polymerase II interaction and couples histone H3 K36 methylation with transcript elongation. Mol Cell Biol 2005; 25(8): 3305–3316 https://doi.org/10.1128/MCB.25.8.3305-3316.2005
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M Li, HP Phatnani, Z Guan, H Sage, AL Greenleaf, P Zhou. Solution structure of the Set2-Rpb1 interacting domain of human Set2 and its interaction with the hyperphosphorylated C-terminal domain of Rpb1. Proc Natl Acad Sci USA 2005; 102(49): 17636–17641 https://doi.org/10.1073/pnas.0506350102
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W Yuan, J Xie, C Long, H Erdjument-Bromage, X Ding, Y Zheng, P Tempst, S Chen, B Zhu, D Reinberg. Heterogeneous nuclear ribonucleoprotein L Is a subunit of human KMT3a/Set2 complex required for H3 Lys-36 trimethylation activity in vivo. J Biol Chem 2009; 284(23): 15701–15707 https://doi.org/10.1074/jbc.M808431200
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S Bhattacharya, MJ Levy, N Zhang, H Li, L Florens, MP Washburn, JL Workman. The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain. Nat Commun 2021; 12(1): 1443 https://doi.org/10.1038/s41467-021-21663-w
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S Bhattacharya, S Wang, D Reddy, S Shen, Y Zhang, N Zhang, H Li, MP Washburn, L Florens, Y Shi, JL Workman, F Li. Structural basis of the interaction between SETD2 methyltransferase and hnRNP L paralogs for governing co-transcriptional splicing. Nat Commun 2021; 12(1): 6452 https://doi.org/10.1038/s41467-021-26799-3
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S Bhattacharya, JJ Lange, M Levy, L Florens, MP Washburn, JL Workman. The disordered regions of the methyltransferase SETD2 govern its function by regulating its proteolysis and phase separation. J Biol Chem 2021; 297(3): 101075 https://doi.org/10.1016/j.jbc.2021.101075
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YL Zhang, JW Sun, YY Xie, Y Zhou, P Liu, JC Song, CH Xu, L Wang, D Liu, AN Xu, Z Chen, SJ Chen, XJ Sun, QH Huang. Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell Res 2018; 28(4): 476–490 https://doi.org/10.1038/s41422-018-0015-9
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Y Zhou, X Yan, X Feng, J Bu, Y Dong, P Lin, Y Hayashi, R Huang, A Olsson, PR Andreassen, HL Grimes, QF Wang, T Cheng, Z Xiao, J Jin, G Huang. Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation. Haematologica 2018; 103(7): 1110–1123 https://doi.org/10.3324/haematol.2018.187708
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X Zuo, B Rong, L Li, R Lv, F Lan, MH Tong. The histone methyltransferase SETD2 is required for expression of acrosin-binding protein 1 and protamines and essential for spermiogenesis in mice. J Biol Chem 2018; 293(24): 9188–9197 https://doi.org/10.1074/jbc.RA118.002851
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L Xu, Y Zheng, X Li, A Wang, D Huo, Q Li, S Wang, Z Luo, Y Liu, F Xu, X Wu, M Wu, Y Zhou. Abnormal neocortex arealization and Sotos-like syndrome-associated behavior in Setd2 mutant mice. Sci Adv 2021; 7(1): eaba1180 https://doi.org/10.1126/sciadv.aba1180
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Y Xie, M Sahin, T Wakamatsu, A Inoue-Yamauchi, W Zhao, S Han, AM Nargund, S Yang, Y Lyu, JJ Hsieh, CS Leslie, EH Cheng. SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis. JCI Insight 2023; 8(4): e154120 https://doi.org/10.1172/jci.insight.154120
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H Yuan, N Li, D Fu, J Ren, J Hui, J Peng, Y Liu, T Qiu, M Jiang, Q Pan, Y Han, X Wang, Q Li, J Qin. Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis. J Clin Invest 2017; 127(9): 3375–3391 https://doi.org/10.1172/JCI94292
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BY Chen, J Song, CL Hu, SB Chen, Q Zhang, CH Xu, JC Wu, D Hou, M Sun, YL Zhang, N Liu, PC Yu, P Liu, LJ Zong, JY Zhang, RF Dai, F Lan, QH Huang, SJ Zhang, SD Nimer, Z Chen, SJ Chen, XJ Sun, L Wang. SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS. Blood 2020; 135(25): 2271–2285 https://doi.org/10.1182/blood.2019001963
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N Niu, P Lu, Y Yang, R He, L Zhang, J Shi, J Wu, M Yang, ZG Zhang, LW Wang, WQ Gao, A Habtezion, GG Xiao, Y Sun, L Li, J Xue. Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis. Gut 2020; 69(4): 715–726 https://doi.org/10.1136/gutjnl-2019-318362
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H Yuan, Y Han, X Wang, N Li, Q Liu, Y Yin, H Wang, L Pan, L Li, K Song, T Qiu, Q Pan, Q Chen, G Zhang, Y Zang, M Tan, J Zhang, Q Li, X Wang, J Jiang, J Qin. SETD2 restricts prostate cancer metastasis by integrating EZH2 and AMPK signaling pathways. Cancer Cell 2020; 38(3): 350–365.e7 https://doi.org/10.1016/j.ccell.2020.05.022
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H Rao, X Li, M Liu, J Liu, W Feng, H Tang, J Xu, WQ Gao, L Li. Multilevel regulation of beta-catenin activity by SETD2 suppresses the transition from polycystic kidney disease to clear cell renal cell carcinoma. Cancer Res 2021; 81(13): 3554–3567 https://doi.org/10.1158/0008-5472.CAN-20-3960
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H Rao, C Liu, A Wang, C Ma, Y Xu, T Ye, W Su, P Zhou, WQ Gao, L Li, X Ding. SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer. Nat Commun 2023; 14(1): 7572 https://doi.org/10.1038/s41467-023-43378-w
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