YTHDF3 modulates hematopoietic stem cells by recognizing RNA m⁶A modification on <i>Ccnd1</i>

Abstract

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.

METTL3 is essential for normal progesterone signaling during embryo implantation via m 6 A-mediated translation control of progesterone receptor

“…6 D ). Studies showed that EIF3 ( 45 ), YTHDF1 ( 47 , 48 ), YTHDF2 ( 46 ) and YTHDF3 ( 49 , 50 ) can serve as m 6 A readers that enhance the translation efficiency of m 6 A-modified mRNAs. Using siRNA screening ( Fig.…”

YTHDF1 promotes gallbladder cancer progression via post‐transcriptional regulation of the m6A/UHRF1 axis

“…It has been reported that IGF2BP1 enhanced mRNA stability by recruiting PABPC1 to the target mRNA 35 . YTHDF3 was additionally proven to bind PABPC1 in haematopoietic cells and enhance Ccnd1 translation 36 . PABPC1 was able to stabilize lncRNA‐PAGBC in gallbladder cancer, and activates the AKT/mTOR pathway to promote tumour growth and metastasis 37 .…”

N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms

“…YTHDF3 is also involved in the regulation of HSCs. YTHDF3 binds m 6 A on the 5’UTR of CCND1 mRNA and cooperates with PABPC1 and EIF4G2 to promote the expression of CCND1, a positive regulator of HSCs reconstitution capacity ( 87 ). While YTHDF3 facilitates the translation of FOXM1 and ASXL1 transcripts and is critical for maintaining HSC properties under stress conditions ( 88 ).…”

“…At present, many experiments have successfully constructed the YTHDF1/2/3 genetic KO mouse model using different techniques. First, the whole-body YTHDF1/2/3 KO mice are generated directly based on CRISPR/Cas9 by deleting a certain exon or inducing the premature appearance of a stop codon ( 87 , 88 , 110 , 213 ). Second, the Cre/LoxP technique is used to generate cell-specific conditional YTHDF1/2/3 KO mice ( 74 , 84 , 108 , 165 , 167 , 174 , 227 , 289 ).…”