Summary: YTHDF2 is a key protein that assists in creating healthy blood cells by regulating the body’s inflammatory response.
Source: University of Edinburgh
The study is the first to reveal a protein that has a crucial role in protecting the blood’s stem cells, which continually produce all blood and immune cells needed in the body, from premature aging.
The discovery shows that the protein, known as YTHDF2, protects these stem cells from damage when the body is fighting an infection and allows them to continue functioning correctly throughout life.
Scientists have long puzzled over how these cells, known as hematopoietic stem cells, protect themselves from burnout whilst ramping up the production of immune cells to combat an infection.
Previous studies found that the YTHDF2 protein has an important role in the development of healthy blood cells, a process known as haematopoiesis.
A team of researchers, jointly led by the University of Edinburgh and Queen Mary University of London, studied mice that lacked YTHDF2 protein to better understand its role in blood stem cells.
They treated YTHDF2 deficient young mice with a chemical that mimics a viral infection to investigate whether the protein had a role during the immune response or inflammation.
The team found that the YTHDF2 deficient mice’s hematopoietic stem cells displayed signs of chronic inflammation that limited their long–term ability to produce new blood cells.
During infections these stem cells produce vast numbers of specialised immune cells.
But the resulting inflammatory process is an emergency response and needs careful regulation to avoid the stem cells from becoming exhausted and unable to function correctly in the future.
The study is the first to reveal that the YTHDF2 protein protects the long-term integrity of hematopoietic stem cells by regulating the activity of genes that drive inflammatory processes.
In the absence of YTHDF2, the damage to the young mice’s stem cells altered the production of blood cell types, causing them to resemble the blood of much older mice.
During the aging process hematopoietic stem cells naturally lose their potency and ability to manufacture new blood cells, leaving older adults more vulnerable to infection.
Further studies are needed to reveal whether manipulating YTHDF2 levels during ageing could help preserve stem cells and improve their ability to fight infections.
The study, carried out in collaboration with Harvard Medical School, Georg-Speyer-Haus and Goethe University, and University of Oxford, was published in the Journal of Experimental Medicine.
Funding: It was supported by Cancer Research UK, Barts Charity and Wellcome.
About this genetics and aging research news
Source: University of Edinburgh
Contact: Press Office – University of Edinburgh
Image: Image credited to Andrejs Ivanovs
Original Research: Open access.
“The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function” by O’Carroll et al. Journal of Experimental Medicine
The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function
The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.