Stage-specific requirement for Mettl3-dependent m 6 A mRNA methylation during haematopoietic stem cell differentiation

Nat Cell Biol. 2019 Jun;21(6):700-709. doi: 10.1038/s41556-019-0318-1. Epub 2019 May 6.

Abstract

Haematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation, but how these functions are precisely regulated is not fully understood. N6-methyladenosine (m6A) messenger RNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deletion of the m6A methyltransferase Mettl3 from the adult haematopoietic system led to an accumulation of HSCs in the bone marrow and a marked reduction of reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not impact myeloid cell number or function. RNA sequencing revealed 2,073 genes with significant m6A modifications in HSCs. Myc was identified as a direct target of m6A in HSCs. Mettl3-deficient HSCs failed to upregulate MYC expression following stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results reveal a key role of m6A in governing HSC differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / genetics
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Cell Differentiation / genetics*
  • Gene Expression Regulation, Developmental / genetics
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Methylation
  • Methyltransferases / genetics*
  • Mice
  • Proto-Oncogene Proteins c-myc / genetics*
  • RNA, Messenger / genetics
  • Sequence Analysis, RNA

Substances

  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • N6-methyladenosine (m6A)
  • Methyltransferases
  • Mettl3 protein, mouse
  • Adenosine