Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC)-stabilized lncRNA small nucleolar RNA host gene 15 (Snhg15) modulates hematopoietic injury induced by γ-ray irradiation via m6A modification

With advancements in radiotherapy technologies, the detrimental effects of ionizing radiation on biological systems, particularly the hematopoietic system, have caused significant concern. N⁶-methyladenosine (m⁶A), the most pervasive representative of post-transcriptional modifications, plays critical roles in diverse biological events. Non-coding RNA comprises the vast majority of the human genome. This study aimed to explore the role of long non-coding RNA (lncRNA) m⁶A modification in γ-ray irradiation-induced hematopoietic injury. By using mouse models, it was found that γ-radiation rapidly damaged hematopoietic bone marrow cells (BMCs), triggering apoptosis, oxidative stress and DNA damage, along with up-regulation of m⁶A Reader proteins. We revealed the time-conditioned landscape of lncRNA m⁶A methylome of BMCs in the short term after radiation and found that a dynamic "change-then-recover" trend involved. LncRNA Snhg15 was identified as a key regulator through integration analysis of the methylome and transcriptome data. Its m⁶A modification was closely related to progression of radiation injury in BMCs. Further research demonstrated that the novel m⁶A Reader LRPPRC could interact with the modification site of Snhg15, stabilize Snhg15 and promote its expression, thereby exacerbating radiation-induced injury to BMCs both in vitro and in vivo. Knockdown of Lrpprc or Snhg15 could alleviate the radiation injury to the hematopoietic system. Additionally, the LRPPRC-Snhg15 axis was involved in the radio-protective efficacy of gut microbiota-derived valeric acid. These findings uncover a novel mechanism by which m⁶A-modified lncRNA Snhg15 is stabilized by LRPPRC modulates γ-irradiation-induced hematopoietic injury, providing potential therapeutic targets for the prevention and treatment of radiation injuries.