Differential m6A RNA landscapes across hematopoiesis reveal a role for IGF2BP2 in preserving hematopoietic stem cell function

N6-methyladenosine (m6A) on mRNA plays critical roles in various cellular processes. However, the landscape and dynamics of m6A modification in hematopoietic system remain unknown. Here, we delineate a comprehensive m6A landscape across hematopoietic hierarchy and uncover that IGF2BP2 is required for preserving the function of hematopoietic stem cells (HSCs). Our data reveal a cell-type-specific m6A landscape in hematopoiesis. m6A modifications arise mostly in the early stage of hematopoiesis and prefer to play distinct roles for determining mRNA fates in HSCs and committed progenitors. Mechanistically, increased m6A-IGF2BP2 expression controls transcriptional state and maintenance of HSCs. IGF2BP2 deficiency induces quiescence loss and impairs HSC function. Moreover, IGF2BP2 loss increases mitochondrial activity of HSCs by accelerating Bmi1 mRNA decay, leading to de-repression of mitochondria-related genes. Collectively, our results present a fascinating portrait of m6A modification of hematopoietic hierarchy and reveal a key role of IGF2BP2 in maintaining HSC function by restraining mitochondrial activity. [Display omitted] •A comprehensive m6A landscape of hematopoietic system is established by SLIM-seq•m6A modification plays different roles in HSCs and committed progenitors•IGF2BP2 is critical in preserving HSCs function by restraining mitochondrial activity•Bmi1 is a functional downstream target of IGF2BP2 in HSCs Yin et al. delineate a comprehensive m6A landscape and dynamics across hematopoietic hierarchy by establishing a super-low-input m6A-seq strategy and reveal IGF2BP2-BMI1 signaling axis in preserving HSC function via regulating mitochondrial activity. This study uncovers a conserved and complicated role of m6A in controlling hematopoietic trajectory.