SETD4, a SET domain-containing protein, functions as a histone lysine methyltransferase. It is involved in multiple biological processes such as regulating cell quiescence, which is crucial for maintaining stem cell reservoirs. It participates in pathways like the PI3K-Akt-mTOR signaling pathway and is important for normal development and homeostasis in various tissues [2,3,4]. Genetic mouse models have been instrumental in understanding its functions.

In gene knockout (KO) and conditional knockout (CKO) mouse models, deletion of Setd4 led to various outcomes. In adult mice, Setd4 deletion improved survival from whole-body irradiation-induced bone marrow failure, with enhanced recovery of hematopoietic stem cells and progenitor cells, indicating its role in hematopoiesis [5]. In the heart, conditional Setd4 knockout in c-Kit-CreERT2;Setd4f/f;Rosa26TdTomato mice increased capillary vascular endothelial cells, and Setd4 knockout in myocardial infarction-injured mice attenuated cardiomyocyte apoptosis and improved cardiac function, showing its importance in cardiac neovascularization and function [4]. In the brain, conditional knockout of Setd4 in adult murine brain resulted in quiescence exit of neural stem cells (NSCs), contributing to damage repair, while long-term deletion or over-expression affected NSC reservoir and neurogenesis [2]. In prostate cancer, decreased SETD4 expression in cells and tissue specimens was associated with inferior clinicopathological characteristics, and knockdown of SETD4 promoted cell proliferation and cell cycle progression, suggesting its role as a tumor suppressor [1].

In summary, SETD4 is essential for maintaining cellular quiescence, regulating stem cell-related processes, and has implications in various disease areas. Studies using KO/CKO mouse models have revealed its role in cancer, hematopoiesis, cardiac function, and neural development, providing valuable insights into potential therapeutic targets for these diseases.

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. 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/

3. 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/

4. 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/

5. 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/