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.

mRNA 上的N ⁶ -甲基腺苷 (m ⁶ A) 在各种细胞过程中起关键作用。然而，造血系统中m ⁶ A 修饰的景观和动力学仍然未知。在这里，我们描绘了一个跨越造血层次的综合 m ⁶ A 景观，并发现 IGF2BP2 是保持造血干细胞 (HSC) 功能所必需的。我们的数据揭示了造血过程中细胞类型特异性的 m ⁶ A 景观。m ⁶ A 修饰主要出现在造血的早期阶段，并且更喜欢在决定 HSC 和定型祖细胞中的 mRNA 命运方面发挥不同的作用。机械地，增加 m ⁶A-IGF2BP2 表达控制 HSC 的转录状态和维持。IGF2BP2 缺乏会导致静止期丧失并损害 HSC 功能。此外，IGF2BP2 缺失通过加速Bmi1 mRNA 衰变增加了 HSC 的线粒体活性，从而导致线粒体相关基因的去抑制。总的来说，我们的研究结果呈现了一幅令人着迷的 m ⁶ A 造血层次修饰图，并揭示了 IGF2BP2 通过抑制线粒体活性在维持 HSC 功能中的关键作用。