SETDB2, short for SET domain bifurcated histone lysine methyltransferase 2, is a histone methyltransferase that methylates histone H3 lysine 9 (H3K9), contributing to the formation of heterochromatin and transcriptional silencing [2]. It is involved in multiple biological processes and associated with pathways like interferon signaling, cell cycle regulation, and NF-κB-mediated inflammation [1,5]. SETDB2 is of great biological importance as its dysregulation is linked to various diseases, making genetic models crucial for studying its functions.

In abdominal aortic aneurysm (AAA) development, myeloid-specific knockout of SETDB2 in mice protected them from AAA formation. This was due to increased expression of tissue inhibitors of metalloproteinases (TIMP1-3) as SETDB2-mediated H3K9me3 repression on their promoters was removed, leading to decreased protease activity and preserved aortic architecture [3]. In breast cancer, depletion of SETDB2 in vitro decreased the breast cancer stem cell population and mammosphere formation, and inhibited breast tumor initiation and growth in vivo [4]. In macrophages during wound repair, myeloid-specific SETDB2-deficient mice showed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters [5]. In coronavirus-induced inflammation, myeloid-specific deletion of SETDB2 in mice led to increased pathologic inflammation following coronavirus infection [6]. In acute leukemia, SETDB2 knockdown in pre-BCR+ ALL cells enhanced sensitivity to kinase and chromatin inhibitors, as SETDB2 overexpression in these cells was required for their maintenance in vitro and in vivo [7].

In conclusion, SETDB2 is a key regulator in multiple biological processes. Its functions in maintaining tissue integrity, regulating cell-cycle, and controlling inflammation are revealed through gene-knockout mouse models. These models have contributed significantly to understanding its roles in diseases such as AAA, breast cancer, and acute leukemia, providing potential therapeutic targets for these conditions.

References:

1. Torrano, Joachim, Al Emran, Abdullah, Hammerlindl, Heinz, Schaider, Helmut. 2019. Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming. In Clinical epigenetics, 11, 43. doi:10.1186/s13148-019-0644-y. https://pubmed.ncbi.nlm.nih.gov/30850015/

2. Padeken, Jan, Methot, Stephen P, Gasser, Susan M. 2022. Establishment of H3K9-methylated heterochromatin and its functions in tissue differentiation and maintenance. In Nature reviews. Molecular cell biology, 23, 623-640. doi:10.1038/s41580-022-00483-w. https://pubmed.ncbi.nlm.nih.gov/35562425/

3. Davis, Frank M, Melvin, William J, Mangum, Kevin, Gudjonsson, Johann E, Gallagher, Katherine A. 2023. The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase-Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development. In Annals of surgery, 278, 426-440. doi:10.1097/SLA.0000000000005963. https://pubmed.ncbi.nlm.nih.gov/37325923/

4. Ying, Liu, Fei, Xie, Jialun, Li, Jing, Li, Jing, Feng. 2020. SETDB2 promoted breast cancer stem cell maintenance by interaction with and stabilization of ΔNp63α protein. In International journal of biological sciences, 16, 2180-2191. doi:10.7150/ijbs.43611. https://pubmed.ncbi.nlm.nih.gov/32549764/

5. Mangum, Kevin D, denDekker, Aaron, Li, Qinmengge, Gudjonsson, Johann, Gallagher, Katherine A. 2024. The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair. In JCI insight, 9, . doi:10.1172/jci.insight.179017. https://pubmed.ncbi.nlm.nih.gov/39435663/

6. Melvin, William J, Audu, Christopher O, Davis, Frank M, Moore, Bethany B, Gallagher, Katherine A. . Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2. In Proceedings of the National Academy of Sciences of the United States of America, 118, . doi:10.1073/pnas.2101071118. https://pubmed.ncbi.nlm.nih.gov/34479991/

7. Lin, Chiou-Hong, Wong, Stephen Hon-Kit, Kurzer, Jason H, Feng, Xuhui, Cleary, Michael L. . SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression. In Cell reports, 23, 1166-1177. doi:10.1016/j.celrep.2018.03.124. https://pubmed.ncbi.nlm.nih.gov/29694893/