YTHDC1, short for YTH domain containing 1, is a nuclear N6-methyladenosine (m6A) reader protein. m6A is a prevalent internal modification of eukaryotic mRNA, and YTHDC1 is involved in multiple RNA-related metabolic processes such as mRNA splicing, export, and stability regulation [1,4]. These functions are crucial for various biological processes like cell proliferation, differentiation, and organismal development, and are also associated with disease-related pathways [1-10]. Genetic models, especially knockout (KO) mouse models, have been instrumental in uncovering its functions.

In mouse models, genetic deletion of Ythdc1 markedly blocks acute myeloid leukemia (AML) development and maintenance, as well as self-renewal of leukemia stem cells (LSCs), indicating its oncogenic role in AML [3]. In lung cancer, YTHDC1 knockdown promoted tumor progression and upregulated FSP1 protein level, leading to ferroptosis resistance, suggesting it as a tumor progression suppressor [2]. In muscle stem cells, absence of Ythdc1 led to an inability to exit quiescence, highlighting its importance in muscle stem cell proliferation [5]. Also, deletion of Ythdc1 in mouse embryonic stem (ES) cells initiated cellular reprogramming to a 2C-like state, revealing its role in maintaining ES cell identity [6].

In conclusion, YTHDC1 plays essential roles in multiple biological processes such as cell proliferation, tumor suppression, and stem cell maintenance. The KO/CKO mouse models have significantly contributed to understanding its functions in diseases like AML, lung cancer, and potentially others. These findings enhance our knowledge of YTHDC1-related biological mechanisms and may provide insights for disease treatment strategies [2,3,5,6].

References:

1. Xiao, Wen, Adhikari, Samir, Dahal, Ujwal, Zhao, Yong-Liang, Yang, Yun-Gui. 2016. Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. In Molecular cell, 61, 507-519. doi:10.1016/j.molcel.2016.01.012. https://pubmed.ncbi.nlm.nih.gov/26876937/

2. Yuan, Shuai, Xi, Shu, Weng, Hong, Zeng, Xian-Tao, Hu, Hailiang. 2023. YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer. In Cell death and differentiation, 30, 2477-2490. doi:10.1038/s41418-023-01234-w. https://pubmed.ncbi.nlm.nih.gov/37903990/

3. Sheng, Yue, Wei, Jiangbo, Yu, Fang, He, Chuan, Qian, Zhijian. . A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex-mediated DNA replication. In Blood, 138, 2838-2852. doi:10.1182/blood.2021011707. https://pubmed.ncbi.nlm.nih.gov/34255814/

4. Roundtree, Ian A, Luo, Guan-Zheng, Zhang, Zijie, Shen, Bin, He, Chuan. 2017. YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs. In eLife, 6, . doi:10.7554/eLife.31311. https://pubmed.ncbi.nlm.nih.gov/28984244/

5. Liu, Jin, Zuo, Hongna, Wang, Ziliu, Wang, Hu, Ju, Zhenyu. 2023. The m6A reader YTHDC1 regulates muscle stem cell proliferation via PI4K-Akt-mTOR signalling. In Cell proliferation, 56, e13410. doi:10.1111/cpr.13410. https://pubmed.ncbi.nlm.nih.gov/36722312/

6. Liu, Jiadong, Gao, Mingwei, He, Jiangping, Bao, Xichen, Chen, Jiekai. 2021. The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity. In Nature, 591, 322-326. doi:10.1038/s41586-021-03313-9. https://pubmed.ncbi.nlm.nih.gov/33658714/