Projects per year
Abstract
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 pro-inflammatory 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.
Original language | English |
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Article number | e20200829 |
Number of pages | 11 |
Journal | Journal of Experimental Medicine |
Volume | 218 |
Issue number | 3 |
DOIs | |
Publication status | Published - 6 Nov 2020 |
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Wellcome Trust Tissue Repair PhD Programme MAIN AWARD
Forbes, S., Hansen, C. & Rossi, A.
11/09/17 → 30/09/23
Project: Research
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RNA regulation and modification in tissue development and homeostasis
24/09/15 → 23/09/22
Project: Research
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`Core Funding for the Wellcome Trust Centre for Cell Biology¿, Research Enrichment, Public Engagement
1/12/18 → 1/06/22
Project: Research
Profiles
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Alex Von Kriegsheim
- Deanery of Molecular, Genetic and Population Health Sciences - Group Leader / Mass Spectrometry Facility Manager
- Edinburgh Cancer Research Centre
Person: Academic: Research Active