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 mA modification.

With advancements in radiotherapy technologies, the detrimental effects of ionizing radiation on biological systems, particularly the hematopoietic system, have caused significant concern. N-methyladenosine (mA), 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) mA 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 mA Reader proteins. We revealed the time-conditioned landscape of lncRNA mA 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 mA modification was closely related to progression of radiation injury in BMCs. Further research demonstrated that the novel mA 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 mA-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.