O'Carroll lab paper featured in the Journal of Experimental Medicine. Authors Mapperley, C., van de Lagemaat, L.N., Lawson, H., Tavosanis, A., Paris, J., Campos, J., Wotherspoon, D., Durko, J., Sarapuu, A., Choe, J., Ivanova, I., Krause, D.S., von Kriegsheim, A., Much, C., Morgan, M., Gregory, R.I., Mead, A.J., O’Carroll, D., and Kranc, K.R. Image The messenger RNA chemical modification N6-methyladenosine (m6A) and its reader YTHDF2 supress proinflammatory gene expression in haematopoietic stem cells to prevent exhaustion and premature ageing. Summary by Lori Koch Chemical modifications to messenger RNAs can determine whether they are translated into protein. The m6A (methyladenosine) modification is the most common internal mRNA modification and it is recognised by “m6A readers” including the protein YTHDF2. Recently, it was discovered that inactivation of YTHDF2 causes an increase in the number of blood stem cells and prevents the initiation and progression of acute myeloid leukemia (AML) in mouse models (Paris et al 2019). It was unknown, however, whether loss of YTHDF2 might affect blood stem cell function long-term. In their recent study published in the Journal of Experimental Medicine, scientists in the Kranc (Queen Mary University of London) and O’Carroll (University of Edinburgh and WCB) groups investigated this using mouse models where they could inducibly deplete YTHDF2 from blood stem cells. They performed transplantation assays in which control or YTHDF2-depleted blood stem cells were transferred to irradiated mice and found that the mutant stem cells failed to repopulate blood cell populations in the recipient mice. When they analysed which genes were expressed in YTHDF2-deficient blood cells, they found many inflammatory response genes were activated and then determined that proteins associated with inflammation were present. Methylation-sequencing showed that many m6A-modified mRNAs involved in the inflammatory response were up-regulated in the absence of YTHDF2. After following YTHDF2-deficient and control mice for one year, the scientists determined that the ability to regenerate B and T cells was almost completely lost in the mutant mice compared to controls. Overall, the research shows that while YTHDF2 is not required for maintenance of essential blood cell populations, it is required for maintaining stem cell regenerative potential. Paris et al. 2019. Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia. Cell Stem Cell 25, 137–148. Related links Journal Link O'Carroll Lab Website DOI This article was published on 2024-06-17
