Mbd2, or methyl-CpG-binding domain 2, is a “reader” protein that interprets DNA methylome-encoded information. It is involved in transcriptional activation/repression, regulation of chromatin structure, and has importance in processes like pluripotency, development, and differentiation [2]. It is associated with pathways such as PI3K/Akt signaling [1,3].

In multiple disease models, Mbd2 has shown significant impacts. In macrophage-specific Mbd2-deficient mice, it protected against bleomycin-induced pulmonary fibrosis, as Mbd2 deficiency attenuated TGF-β1 production and reduced M2 macrophage accumulation. Mechanistically, Mbd2 bound to the Ship promoter, repressed Ship expression, and enhanced PI3K/Akt signaling to promote the macrophage M2 program [1]. In MMTV-PyMT transgenic mice with Mbd2 genetic knockout, primary tumor growth and lung metastasis were impeded, and the expression of epithelial-to-mesenchymal transition-related determinants was abrogated, along with impairment of the PI3K/AKT pathway activation [3]. Also, in septic AKI models, Mbd2-knockout mice had improved survival rate, attenuated renal cell apoptosis, and reduced inflammatory factor production, with Mbd2 directly binding to the promoter region of PKCη to regulate its expression and activate PKCη/p38MAPK and ERK1/2 axis [4].

In conclusion, Mbd2 is crucial in regulating various biological processes and its dysregulation is associated with diseases like pulmonary fibrosis, cancer, and septic AKI. Gene knockout mouse models have been instrumental in uncovering Mbd2's role in these disease conditions, highlighting its potential as a therapeutic target in clinical settings [1,3,4].

References:

1. Wang, Yi, Zhang, Lei, Wu, Guo-Rao, Xiong, Weining, Wang, Cong-Yi. 2021. MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program. In Science advances, 7, . doi:10.1126/sciadv.abb6075. https://pubmed.ncbi.nlm.nih.gov/33277324/

2. Menafra, Roberta, Stunnenberg, Hendrik G. 2014. MBD2 and MBD3: elusive functions and mechanisms. In Frontiers in genetics, 5, 428. doi:10.3389/fgene.2014.00428. https://pubmed.ncbi.nlm.nih.gov/25538734/

3. Mahmood, Niaz, Arakelian, Ani, Szyf, Moshe, Rabbani, Shafaat A. 2024. Methyl-CpG binding domain protein 2 (Mbd2) drives breast cancer progression through the modulation of epithelial-to-mesenchymal transition. In Experimental & molecular medicine, 56, 959-974. doi:10.1038/s12276-024-01205-2. https://pubmed.ncbi.nlm.nih.gov/38556549/

4. Xie, Yuxin, Liu, Bohao, Pan, Jian, Dong, Zheng, Zhang, Dongshan. 2020. MBD2 Mediates Septic AKI through Activation of PKCη/p38MAPK and the ERK1/2 Axis. In Molecular therapy. Nucleic acids, 23, 76-88. doi:10.1016/j.omtn.2020.09.028. https://pubmed.ncbi.nlm.nih.gov/33335794/