Suv39h1-KO Mouse

Suv39h1, a lysine methyltransferase, is known for its role in introducing di-and trimethylation at histone H3 lysine 9 (H3K9). It is crucial in maintaining heterochromatin and gene repression, and is involved in various biological processes [6]. Genetic models, such as KO and CKO mouse models, have been valuable in studying its functions.

In liver fibrosis, HSC-specific or myofibroblast-specific deletion of Suv39h1 in mice ameliorated liver fibrosis. Suv39h1 inhibition by chaetocin also mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed its transcription [1]. In adoptive T-cell therapies, genetic disruption of SUV39H1 enhanced the early expansion, long-term persistence, and overall antitumor efficacy of human CAR T cells in leukemia and prostate cancer models [2]. Also, in solid tumor models, inactivation of SUV39H1 enhanced BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges [3]. In limb ischemia of mice, pharmaceutical inhibition or genetic deletion of SUV39H1 significantly improved blood perfusion, capillary density, and angiogenesis in ischemic muscle tissue [4]. In liver ischemia-reperfusion injury, global or hepatocyte conditional Suv39h1 KO mice were protected from liver I/R injury, and a small-molecule SUV39H1 inhibitor achieved similar hepatoprotective effects [5]. In MLL-AF9-induced AML, Suv39h1 overexpression increased leukemia latency and decreased the frequency of LSCs, while Suv39h1 knockdown accelerated disease progression [7]. In glioblastoma, knockdown of SUV39H1 in patient-derived GSCs impaired their proliferation and stemness, and treatment with a SUV39H1 inhibitor sensitized GSCs to temozolomide [8].

In conclusion, Suv39h1 plays essential roles in multiple biological processes and diseases. Model-based research, especially through Suv39h1 KO/CKO mouse models, has revealed its significance in liver fibrosis, adoptive T-cell therapies for cancer, limb ischemia, liver ischemia-reperfusion injury, AML, and glioblastoma. Understanding Suv39h1 functions provides potential therapeutic targets for these disease areas.

References:

1. Kong, Ming, Zhou, Junjing, Kang, Aoqi, Xu, Yong, Li, Zilong. 2024. Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis. In Gut, 73, 810-824. doi:10.1136/gutjnl-2023-329671. https://pubmed.ncbi.nlm.nih.gov/38176898/

2. Jain, Nayan, Zhao, Zeguo, Koche, Richard P, Giavridis, Theodoros, Sadelain, Michel. . Disruption of SUV39H1-Mediated H3K9 Methylation Sustains CAR T-cell Function. In Cancer discovery, 14, 142-157. doi:10.1158/2159-8290.CD-22-1319. https://pubmed.ncbi.nlm.nih.gov/37934007/

3. López-Cobo, Sheila, Fuentealba, Jaime R, Gueguen, Paul, Saitakis, Michael, Amigorena, Sebastian. . SUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors. In Cancer discovery, 14, 120-141. doi:10.1158/2159-8290.CD-22-1350. https://pubmed.ncbi.nlm.nih.gov/37934001/

4. Niu, Wenhao, Cao, Wenyue, Wu, Feng, Liang, Chun. . SUV39H1 Inhibits Angiogenesis in Limb Ischemia of Mice. In Cell transplantation, 32, 9636897231198167. doi:10.1177/09636897231198167. https://pubmed.ncbi.nlm.nih.gov/37811706/

5. Li, Zilong, Li, Jichen, Wu, Meng, Qin, Lei, Fan, Zhiwen. 2024. Redox-sensitive epigenetic activation of SUV39H1 contributes to liver ischemia-reperfusion injury. In Redox biology, 78, 103414. doi:10.1016/j.redox.2024.103414. https://pubmed.ncbi.nlm.nih.gov/39603205/

6. Weirich, Sara, Khella, Mina S, Jeltsch, Albert. 2021. Structure, Activity and Function of the Suv39h1 and Suv39h2 Protein Lysine Methyltransferases. In Life (Basel, Switzerland), 11, . doi:10.3390/life11070703. https://pubmed.ncbi.nlm.nih.gov/34357075/

7. Chu, Yajing, Chen, Yangpeng, Guo, Huidong, Shi, Jun, Yuan, Weiping. 2020. SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia. In Oncogene, 39, 7239-7252. doi:10.1038/s41388-020-01495-6. https://pubmed.ncbi.nlm.nih.gov/33037410/

8. Li, Chunying, Xie, Qiqi, Ghosh, Sugata, Nephew, Kenneth P, Shen, Jia. 2024. SUV39H1 Preserves Cancer Stem Cell Chromatin State and Properties in Glioblastoma. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.08.15.607856. https://pubmed.ncbi.nlm.nih.gov/39229036/