Gamma-irradiation fluctuates the mRNA N-methyladenosine (mA) spectrum of bone marrow in hematopoietic injury.

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 mA 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 mA methylome functions in the hematopoietic system after irradiation remains ambiguous. Here, we uncovered the time-varying epitranscriptome-wide mA 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 mA content and expression of mA related enzymes were altered. Gamma-irradiation triggered dynamic and reversible mA modification profiles and altered mRNA expression, where both mA fold-enrichment and mRNA expression most followed the (5 min_up/2 h_down) pattern. The CDS enrichment region preferentially upregulated mA peaks at 5 min. Moreover, the main GO and KEGG pathways were closely related to metabolism and the classical radiation response. Finally, mA modifications correlated with transcriptional regulation of genes in multiple aspects. Blocking the expression of mA demethylases FTO and ALKBH5 mitigated radiation hematopoietic toxicity. Together, our findings present the comprehensive landscape of mRNA mA methylation in the mouse hematopoietic system in response to γ-irradiation, shedding light on the significance of mA modifications in mammalian radiobiology. Regulation of the epitranscriptome may be exploited as a strategy against radiation damage.