The Role Of RNA Methylation Reader Gene YTHDF2 In Hematopoietic Stem Cell Regeneration And Maintenance

Adult hematopoietic stem cells(HSC)maintain the body under different stress conditions,such as injury,inflammation,hemorrhage,aging and so on.In addition,HSCs timely supplement the mature cells of the blood system components to deal with the physiological needs of the body.Single-cellomics analysis has revealed that hematopoietic stem cells are a heterogeneous population with long-term self-renewal and multi-directional differentiation.HSC is a stem cell type with the longest research history and the deepest mechanism analysis in adult stem cells.Its research has the research on other types of stem cells(small intestine,muscle,nerve,cancer stem cells,etc.)and some blood diseases.Important guiding significance.However,the in vitro expansion of HSC has not been achieved so far,and the molecular mechanism of HSC steady-state maintenance and pressure response in vivo remains to be elucidated.In eukaryotic cells,6-methyladenine(m6A)is one of the most abundant methylated modifications in the chemical modification of mRNAs found to date.Previous molecular and biochemical studies have found that there are approximately 3-5 m6 A modifications per mRNA in eukaryotic cells.The m6 A methylation modification of mRNA is currently considered to be dynamically reversible.Because the cells contain m6 A methyltransferases METTL3,METTL14 and WTAP and two demethylating enzymes ALKBH5 and FTO.In addition,the discovery of m6 A demethylase and methyltransferase and the development of corresponding knockout mice have greatly promoted the study of the role and function of m6 A modification in different fields,while The research of the m6 A reader is relatively small.The m6 A readers have found include YTHDF1,YTHDF2,and YTHDF3 which is localized in the cytoplasm,and YTHDC1 and YTHDC2 which is localized in the nucleus.The cytoplasmic m6 A readers YTHDF2 and YTHDF1,YTHDF3 were reported to be involved in the degradation and translation of mRNA.However,little is known about the functional study of the m6 A cytoplasmic reader YTHDF2 in hematopoietic stem cells.We used a hematopoietic-specific YTHDF2 knockout mouse model to analyze the effects ofYTHDF2 deletion on HSC phenotype and function.We found that the absence of YTHDF2 promoted the proliferation of adult HSCs and also enhanced their ability to self-renew.Further,under the hematopoietic pressure of 5-FU and IR,we also found that YTHDF2 deletion can promote the regeneration and anti-apoptosis ability of adult HSC.Finally,we found through transcriptomics that YTHDF2 regulates the degradation of Wnt pathway and anti-apoptotic pathway-related mRNA to affect HSC function.This study demonstrates that the Wnt pathway and anti-apoptotic pathway-related molecules in hematopoietic stem cells depend on the mRNA degradation mechanism of the m6 A reader YTHDF2.At the same time,it provides a basis for further study on the biological function and RNA epigenetics of m6 A and its related molecules,as well as normal physiology(such as stem cell dry maintenance and differentiation)or abnormal pathological life activities(such as malignant tumors,aging-related diseases,etc.).The related molecular mechanism provides a new research direction.