Tet3, also known as ten-eleven translocation methylcytosine dioxygenase 3, is a key enzyme responsible for 5-methylcytosine oxidation and DNA demethylation. It plays a vital role in early zygote formation, embryogenesis, and neuronal differentiation. DNA demethylation mediated by Tet3 is involved in multiple biological processes, regulating gene expression and cell fate commitment [4]. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying Tet3's functions.

In KO mouse models, selective depletion of Tet3 in adipose precursor cells reduces adipogenesis, protects against diet-induced adipose expansion, and enhances whole-body metabolism, indicating its role in white adipose development [3]. Intestinal epithelial cell-specific ablation of Tet3 (Tet3ΔIEC) mice show decreased innate immune response, Paneth cell differentiation, and epithelial regeneration, and increased susceptibility to enteric pathogen infection and experimental colitis, highlighting its importance in gut epithelial response to stressors [5]. Myeloid-specific Tet3 ablation in mice strongly inhibits endometriosis progression, suggesting Tet3-overexpressing macrophages as key pathogenic contributors to endometriosis [1]. Mouse progenies derived from oocytes of maternal Tet3 deletion display glucose intolerance, demonstrating the role of oocyte Tet3 in offspring glucose homeostasis [2].

In conclusion, Tet3 is essential for multiple biological processes, including adipogenesis, gut epithelial response, endometriosis development, and glucose homeostasis in offspring. The use of Tet3 KO/CKO mouse models has significantly advanced our understanding of its functions in these specific disease areas, providing potential therapeutic targets for related diseases.

References:

1. Lv, Haining, Liu, Beibei, Dai, Yangyang, Taylor, Hugh S, Huang, Yingqun. 2024. TET3-overexpressing macrophages promote endometriosis. In The Journal of clinical investigation, 134, . doi:10.1172/JCI181839. https://pubmed.ncbi.nlm.nih.gov/39141428/

2. Chen, Bin, Du, Ya-Rui, Zhu, Hong, Xu, Guo-Liang, Huang, Hefeng. 2022. Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency. In Nature, 605, 761-766. doi:10.1038/s41586-022-04756-4. https://pubmed.ncbi.nlm.nih.gov/35585240/

3. Jung, Byung Chul, You, Dongjoo, Lee, Ikjun, Banks, Alexander S, Kang, Sona. 2023. TET3 plays a critical role in white adipose development and diet-induced remodeling. In Cell reports, 42, 113196. doi:10.1016/j.celrep.2023.113196. https://pubmed.ncbi.nlm.nih.gov/37777963/

4. Beck, David B, Petracovici, Ana, He, Chongsheng, Bonasio, Roberto, Fahrner, Jill A. 2020. Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency. In American journal of human genetics, 106, 234-245. doi:10.1016/j.ajhg.2019.12.007. https://pubmed.ncbi.nlm.nih.gov/31928709/

5. Gonzalez, Edward A, Liu, Yue, Wang, Dahui, Gao, Nan, Etchegaray, Jean-Pierre. 2023. TET3-mediated DNA oxidation is essential for intestinal epithelial cell response to stressors. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2221405120. doi:10.1073/pnas.2221405120. https://pubmed.ncbi.nlm.nih.gov/37669386/