Humans benefit from nuclear technologies but consequently experience nuclear disasters or side effects of iatrogenic radiation. Hematopoietic system injury first arises upon radiation exposure. As an intricate new layer of genetic control, the posttranscriptional m6A modification of RNA has recently come under investigation and has been demonstrated to play pivotal roles in multiple physiological and
pathological processes. However, how the
m6A methylome functions in the hematopoietic system after irradiation remains ambiguous. Here, we uncovered the time-varying epitranscriptome-wide
m6A methylome and transcriptome alterations in γ-ray-exposed mouse bone marrow. 4 Gy γ-irradiation rapidly (5 min and 2 h) and severely impaired the mouse hematopoietic system, including spleen and thymus weight, blood components, tissue
inflammation and
malondialdehyde (MDA) levels. The
m6A content and expression of
m6A related
enzymes were altered. Gamma-irradiation triggered dynamic and reversible
m6A modification profiles and altered
mRNA expression, where both
m6A fold-enrichment and
mRNA expression most followed the (5 min_up/2 h_down) pattern. The CDS enrichment region preferentially upregulated
m6A peaks at 5 min. Moreover, the main GO and KEGG pathways were closely related to metabolism and the classical radiation response. Finally,
m6A modifications correlated with transcriptional regulation of genes in multiple aspects. Blocking the expression of
m6A demethylases FTO and ALKBH5 mitigated radiation hematopoietic toxicity. Together, our findings present the comprehensive landscape of
mRNA m6A methylation in the mouse hematopoietic system in response to γ-irradiation, shedding light on the significance of
m6A modifications in mammalian radiobiology. Regulation of the epitranscriptome may be exploited as a strategy against radiation damage.