Zuo Hongna, Liu Jin, Shen Bin, Sheng Yue, Ju Zhenyu, Wang Hu
Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, The Third People's Hospital of Deqing, Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China.
Cell Death Discov. 2024 Oct 16;10(1):439. doi: 10.1038/s41420-024-02203-z.
YTHDC1, a reader of N6-methyladenosine (mA) modifications on RNA, is posited to exert significant influence over RNA metabolism. Despite its recognized importance, the precise function and underlying mechanisms of YTHDC1 in the preservation of normal hematopoietic stem cell (HSCs) homeostasis remain elusive. Here, we investigated the role of YTHDC1 in normal hematopoiesis and HSCs maintenance in vivo. Utilizing conditional Ythdc1 knockout mice and Ythdc1/Mettl3 double knockout mice, we demonstrated that YTHDC1 is required for HSCs maintenance and self-renewal by regulating microRNA maturation. YTHDC1 deficiency resulted in HSCs apoptosis. Furthermore, we uncovered that YTHDC1 interacts with HP1BP3, a nuclear RNA binding protein involved in microRNA maturation. Deletion of YTHDC1 brought about significant alterations in microRNA levels. However, over-expression of mir-125b, mir-99b, and let-7e partially rescued the functional defect of YTHDC1-null HSCs. Taken together, these findings indicated that the nuclear protein YTHDC1-HP1BP3-microRNA maturation axis is essential for the long-term maintenance of HSCs.
YTHDC1是一种RNA上N6-甲基腺苷（mA）修饰的识别蛋白，被认为对RNA代谢有重大影响。尽管其重要性已得到认可，但YTHDC1在维持正常造血干细胞（HSC）稳态中的精确功能和潜在机制仍不清楚。在这里，我们研究了YTHDC1在体内正常造血和HSC维持中的作用。利用条件性Ythdc1基因敲除小鼠和Ythdc1/Mettl3双基因敲除小鼠，我们证明YTHDC1通过调节微小RNA成熟对HSC的维持和自我更新是必需的。YTHDC1缺陷导致HSC凋亡。此外，我们发现YTHDC1与HP1BP3相互作用，HP1BP3是一种参与微小RNA成熟的核RNA结合蛋白。YTHDC1的缺失导致微小RNA水平发生显著变化。然而，mir-125b mir-99b和let-7e的过表达部分挽救了YTHDC1缺失的HSC的功能缺陷。综上所述，这些发现表明核蛋白YTHDC1-HP1BP3-微小RNA成熟轴对HSC的长期维持至关重要。
