Open AccessYTHDF3 modulates hematopoietic stem cells by recognizing RNA m<sup>6</sup>A modification on <i>Ccnd1</i>
Author(s) -
Xiaofei Zhang,
Tingting Cong,
Lei Wei,
Bixi Zhong,
Xiaowo Wang,
Jian-he Sun,
Shuxia Wang,
Meng Xu,
Ping Zhu,
Hong Jiang,
Jianwei Wang
Publication year - 2022
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2021.279739
Subject(s) - haematopoiesis , biology , stem cell , rna , microbiology and biotechnology , hematopoietic stem cell , gene , cancer research , genetics
Hematopoietic stem cells (HSCs) build up the blood system throughout lifespan. N6-methyladenosine (m6A), the most prevalent RNA modification, modulates gene expression via the processes of “writing” and “reading”. Recent studies showed that m6A “writer” genes (Mettl3 and Mettl14) play an essential role in HSCs. However, which reader deciphers the m6A modification to modulate HSCs remains unknown. In this study, we observed that dysfunction of Ythdf3 and Ccnd1 severely impaired the reconstitution capacity of HSCs, which phenocopies Mettl3 deficient HSCs. Dysfunction of Ythdf3 and Mettl3 results in the translational defect of Ccnd1. Ythdf3 and Mettl3 regulates HSCs by transmitting m6A RNA methylation on the 5’UTR of Ccnd1. Enforced Ccnd1 completely rescues the defect of Ythdf3-/- HSCs and partially rescues Mettl3-compromised HSCs. Taken together, this study for the first time identified that Ccnd1 is the target of METTL3 and YTHDF3 to transmit m6A RNA methylation signal to regulate HSCs reconstitution capacity.