ABSTRACT
Hematopoietic development is tightly regulated by various factors. The role of RNA m6A modification during fetal hematopoiesis, particularly in megakaryopoiesis, remains unclear. Here, we demonstrate that loss of m6A methyltransferase METTL3 induces formation of double-stranded RNAs (dsRNAs) and activates acute inflammation during fetal hematopoiesis in mouse. This dsRNA-mediated inflammation leads to acute megakaryopoiesis, which facilitates the generation of megakaryocyte progenitors but disrupts megakaryocyte maturation and platelet production. The inflammation and immune response activate the phosphorylation of STAT1 and IRF3, and upregulate downstream interferon-stimulated genes (ISGs). Inflammation inhibits the proliferation rate of hematopoietic progenitors and further skews the cell fate determination toward megakaryocytes rather than toward erythroid from megakaryocyte-erythroid progenitors (MEPs). Transcriptional-wide gene expression analysis identifies IGF1 as a major factor whose reduction is responsible for the inhibition of megakaryopoiesis and thrombopoiesis. Restoration of IGF1 with METTL3-deficient hematopoietic cells significantly increases megakaryocyte maturation. In summary, we elucidate that the loss of RNA m6A modification-induced acute inflammation activates acute megakaryopoiesis, but impairs its final maturation through the inhibition of IGF1 expression during fetal hematopoiesis.
Footnotes
Author contributions
Conceptualization: H.-B.L., Y.G.; Data curation: J.S., Y.G.; Formal analysis: X.H., S.L., J.S., Y.G.; Funding acquisition: Y.G.; Investigation: X.H., Y.H., Y.G.; Methodology: X.F., Y.S., C.L., Y.G.; Project administration: Y.G.; Supervision: Y.G.; Validation: S.L., Y.J., R.Y., Y.W.; Visualization: J.S., Y.G.; Writing – original draft: Y.G.; Writing – review & editing: X.H., Y.H., X.F., Y.S., Y.G.
Diversity & Inclusion
The authors support inclusive, diverse, and equitable conduct of research.
Funding
This work was supported by the National Natural Science Foundation of China (32471163/82200119 to Y.G. and 82111540277/82030042/32070917 to H.-B.L.) and the Fundamental Research Funds for the Central Universities (22120240435), and by the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai. X.F. was supported by Guangdong High-level Hospital Construction Foundation (ynkt2021-zz05) and by Shenzhen Science and Technology Program (JCYJ20210324142201004).
Data availability
All relevant data and resource can be found within the article and its supplementary information.