YTHDF3 modulates hematopoietic stem cells by recognizing RNA m<sup>6</sup>A modification on <i>Ccnd1</i>
Xiaofei Zhang,
Tingting Cong,
Lei Wei,
Bixi Zhong,
Xiaowo Wang,
Jin Sun,
Shuxia Wang,
Meng Michelle Xu,
Ping Zhu,
Hong Jiang,
Jianwei Wang
Affiliations
Xiaofei Zhang
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084
Tingting Cong
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084
Lei Wei
Ministry of Education Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Bioinformatics Division, BNRIST, Department of Automation, Tsinghua University, Beijing
Bixi Zhong
Ministry of Education Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Bioinformatics Division, BNRIST, Department of Automation, Tsinghua University, Beijing
Xiaowo Wang
Ministry of Education Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Bioinformatics Division, BNRIST, Department of Automation, Tsinghua University, Beijing
Jin Sun
Department of Geriatrics, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing
Shuxia Wang
Department of Geriatrics, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing
Meng Michelle Xu
Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing
Ping Zhu
Department of Geriatrics, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing
Hong Jiang
Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University 310003
Jianwei Wang
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084
Hematopoietic stem cells (HSC) give rise to the cells of the blood system over the whole 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 HSC. However, which reader deciphers the m6A modification to modulate HSC remains unknown. In this study, we observed that dysfunction of Ythdf3 and Ccnd1 severely impaired the reconstitution capacity of HSC, which phenocopies Mettl3-deficient HSC. Dysfunction of Ythdf3 and Mettl3 results in a translational defect of Ccnd1. Ythdf3 and Mettl3 regulate HSC by transmitting m6A RNA methylation on the 5’ untranslated region of Ccnd1. Enforced Ccnd1 expression completely rescued the defect of Ythdf3-/- HSC and partially rescued Mettl3-compromised HSC. Taken together, this study identified, for the first time, that Ccnd1 is the target of METTL3 and YTHDF3 to transmit the m6A RNA methylation signal and thereby regulate the reconstitution capacity of HSC.
