SETD4, a SET-domain-containing protein, functions as a histone lysine methyltransferase and is involved in epigenetic regulation, playing a significant role in various biological processes. It is associated with pathways such as the Akt signaling pathway, PI3K-Akt-mTOR signaling pathway, and is crucial for maintaining cellular quiescence [1,2,3,5,8,9]. Genetic models, especially KO/CKO mouse models, have been instrumental in studying its functions.

In prostate cancer, SETD4 knockdown promotes cell proliferation and cell cycle progression, while SETD4 represses NUPR1 transcription by methylating H3K27, inactivating the Akt pathway and inhibiting tumorigenesis [1]. In the context of apoptosis, SETD4-mediated KU70 methylation at K570 suppresses apoptosis [2]. Conditional knockout of Setd4 in adult mice leads to quiescence exit of neural stem cells, generating new neurons in the olfactory bulb and contributing to damage repair, while long-term deletion or over-expression affects neurogenesis [3]. In pancreatic development, SETD4-expressing cells contribute to pancreatic lineages and acinar cell regeneration after cerulein-induced pancreatitis [4]. In NSCLC, SETD4-positive cells are quiescent lung cancer stem cells, and SETD4 confers chemoresistance, tumor progression, and a poor prognosis [5]. Deletion of Setd4 in adult mice improves the survival of whole-body irradiation-induced BM failure, and Setd4-deficient mice are better recipients for allogeneic HSC transplantation [6]. Loss of Setd4 delays radiation-induced thymic lymphoma in mice [7]. Conditional knockout of Setd4 in c-Kit-CreERT2;Setd4f/f;Rosa26TdTomato mice increases capillary vascular endothelial cells, and in myocardial infarction injured mice, it attenuates cardiomyocyte apoptosis and improves cardiac function [8]. SETD4 knockout in BMSCs promotes their proliferation but impairs migration, differentiation, and angiogenesis, with changes in genomic methylation [9].

In summary, SETD4 is essential for maintaining cellular quiescence, and its epigenetic regulation impacts various biological processes and disease conditions. The KO/CKO mouse models have revealed its roles in cancer development, apoptosis, tissue development and repair, hematopoiesis, and lymphomagenesis, providing valuable insights into potential therapeutic targets for related diseases. [1-9]

References:

1. Wang, Chong, Wang, Tao, Li, Kang-Jing, Jiang, Yong, Zhao, Shan-Chao. 2023. SETD4 inhibits prostate cancer development by promoting H3K27me3-mediated NUPR1 transcriptional repression and cell cycle arrest. In Cancer letters, 579, 216464. doi:10.1016/j.canlet.2023.216464. https://pubmed.ncbi.nlm.nih.gov/37879429/

2. Wang, Yuan, Liu, Bochao, Lu, Huimei, Montelione, Gaetano T, Shen, Zhiyuan. . SETD4-mediated KU70 methylation suppresses apoptosis. In Cell reports, 39, 110794. doi:10.1016/j.celrep.2022.110794. https://pubmed.ncbi.nlm.nih.gov/35545041/

3. Cai, Sun-Li, Yang, Yao-Shun, Ding, Yan-Fu, Yang, Jin-Shu, Yang, Wei-Jun. 2022. SETD4 cells contribute to brain development and maintain adult stem cell reservoir for neurogenesis. In Stem cell reports, 17, 2081-2096. doi:10.1016/j.stemcr.2022.07.017. https://pubmed.ncbi.nlm.nih.gov/36027907/

4. Tian, Jin-Ze, Xing, Sheng, Feng, Jing-Yi, Yang, Jin-Shu, Yang, Wei-Jun. 2021. SETD4-expressing cells contribute to pancreatic development and response to cerulein induced pancreatitis injury. In Scientific reports, 11, 12614. doi:10.1038/s41598-021-92075-5. https://pubmed.ncbi.nlm.nih.gov/34131249/

5. Wang, Yuehong, Yu, Yuman, Yang, Weijun, Lu, Qianyun, Zhou, Jianying. 2023. SETD4 Confers Cancer Stem Cell Chemoresistance in Nonsmall Cell Lung Cancer Patients via the Epigenetic Regulation of Cellular Quiescence. In Stem cells international, 2023, 7367854. doi:10.1155/2023/7367854. https://pubmed.ncbi.nlm.nih.gov/37274024/

6. Feng, Xing, Lu, Huimei, Yue, Jingyin, Denzin, Lisa K, Shen, Zhiyuan. 2020. Deletion of Mouse Setd4 Promotes the Recovery of Hematopoietic Failure. In International journal of radiation oncology, biology, physics, 107, 779-792. doi:10.1016/j.ijrobp.2020.03.026. https://pubmed.ncbi.nlm.nih.gov/32259569/

7. Feng, Xing, Lu, Huimei, Yue, Jingyin, De, Subhajyoti, Shen, Zhiyuan. 2019. Loss of Setd4 delays radiation-induced thymic lymphoma in mice. In DNA repair, 86, 102754. doi:10.1016/j.dnarep.2019.102754. https://pubmed.ncbi.nlm.nih.gov/31794893/

8. Xing, Sheng, Tian, Jin-Ze, Yang, Shu-Hua, Yang, Jin-Shu, Yang, Wei-Jun. 2021. Setd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation. In Scientific reports, 11, 11603. doi:10.1038/s41598-021-91105-6. https://pubmed.ncbi.nlm.nih.gov/34079011/

9. Liao, Xiaomin, Wu, Caixia, Shao, Zhongming, Guo, Junli, Jie, Wei. 2021. SETD4 in the Proliferation, Migration, Angiogenesis, Myogenic Differentiation and Genomic Methylation of Bone Marrow Mesenchymal Stem Cells. In Stem cell reviews and reports, 17, 1374-1389. doi:10.1007/s12015-021-10121-1. https://pubmed.ncbi.nlm.nih.gov/33506343/