SETDB2, also known as SET domain bifurcated histone lysine methyltransferase 2, is a histone methyltransferase. It methylates histone H3 lysine 9 (H3K9), contributing to the formation of heterochromatin and transcriptional silencing. SETDB2 is involved in multiple biological pathways, including those related to tissue differentiation, metabolism, and inflammation, and plays a crucial role in maintaining normal cellular functions and organismal homeostasis [1]. Genetic models, such as KO/CKO mouse models, are valuable tools for studying SETDB2's functions.

In a myeloid-specific SETDB2 deficient murine model, macrophage-specific knockout of SETDB2 protected mice from abdominal aortic aneurysm (AAA) formation. SETDB2 upregulation in aortic monocyte/macrophages led to suppression of TIMP1-3 transcription through histone 3 lysine 9 trimethylation, increasing matrix metalloproteinase activity. Genetic depletion of SETDB2 increased TIMP expression, decreased protease activity, and preserved aortic architecture [2].

In another study, myeloid cell-specific SETDB2-deficient mice showed that SETDB2 in macrophages drives tissue repair by repressing NF-κB-mediated inflammation. SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters [3].

In conclusion, SETDB2 is essential for multiple biological processes. Through model-based research, especially KO/CKO mouse models, we've learned that SETDB2 is crucial in regulating macrophage-mediated processes in diseases like AAA and wound repair. These findings contribute to our understanding of the role of SETDB2 in specific disease areas and may provide potential therapeutic targets.