YTHDC1-mediated microRNA maturation is essential for hematopoietic stem cells maintenance.

IF 6.1 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2024-10-16 DOI:10.1038/s41420-024-02203-z

Hongna Zuo, Jin Liu, Bin Shen, Yue Sheng, Zhenyu Ju, Hu Wang

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Abstract

YTHDC1, a reader of N6-methyladenosine (m⁶A) 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.

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YTHDC1 介导的 microRNA 成熟对造血干细胞的维持至关重要。

YTHDC1是RNA上N6-甲基腺苷（m6A）修饰的阅读器，被认为对RNA代谢有重大影响。尽管YTHDC1的重要性已得到公认，但它在维持正常造血干细胞（HSCs）稳态方面的确切功能和内在机制仍未确定。在这里，我们研究了YTHDC1在体内正常造血和造血干细胞维持中的作用。利用条件性 Ythdc1 基因敲除小鼠和 Ythdc1/Mettl3 双基因敲除小鼠，我们证明了 YTHDC1 是造血干细胞维持和自我更新所必需的，它通过调节 microRNA 的成熟来实现。YTHDC1 缺乏会导致造血干细胞凋亡。此外，我们还发现YTHDC1与HP1BP3相互作用，HP1BP3是一种参与microRNA成熟的核RNA结合蛋白。YTHDC1的缺失会导致microRNA水平的显著改变。然而，mir-125b、mir-99b和let-7e的过度表达部分挽救了YTHDC1缺失造血干细胞的功能缺陷。综上所述，这些发现表明核蛋白YTHDC1-HP1BP3-microRNA成熟轴对造血干细胞的长期维持至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.