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LncRNA and mRNA profiling in radiated mice bone marrow and hypothalamus pretreated with radioprotectants

ABSTRACT: To further understanding of lncRNA and mRNA expression during radioprotectation, we used microarray analysis to determine the differential expression of lncRNAs, and mRNAs in the bone marrow of mice exposed to high-dose IR with and without pretreatment with three types of radioprotectants: Amifostine, CBLB502, and Nilestriol, as well in the hypothalamus of mice exposed to IR with and without pretreatment with amifostine. Overall, the induction of lncRNAs and mRNAs was increased by pretreatment with all three radioprotectants. Amifostine treatment led to a similar expression pattern of lncRNAs, and mRNAs to that of CBLB502 but not to that of nilestriol. The radioprotectants exhibited mostly opposite effects against IR-induced lncRNAs, and mRNAs in bone marrow, and might induce a potential common mechanism of histone gene downregulation only in the face of IR, mainly via nucleosome assembly and related signaling pathways, which may be a common response to IR-induced biological changes and could explain the radioprotection mechanism. These results expand the biological function of lncRNAs, and mRNAs in mediating the activity of radioprotectants, further offering insights into the molecular mechanism underlying radioprotection.

ORGANISM(S): Mus musculus

PROVIDER: GSE137011 | GEO | 2019/09/07

REPOSITORIES: GEO

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Project description:DNA damage response (DDR) is a complex process, essential for cell survival. Especially deleterious type of DNA damage are DNA double-strand breaks (DSB), which can lead to genomic instability and malignant transformation if not repaired correctly. The central player in DSB detection and repair is the ATM kinase which orchestrates the action of several downstream factors. Despite substantial knowledge of DNA repair processes, still several aspects of DNA damage detection and signaling are not fully understood. Recent studies have suggested that long non-coding RNAs (lncRNAs) are involved in DDR. Here, we aimed to identify lncRNAs induced upon DNA damage in an ATM-dependent manner. 7 mRNAs and 10 lncRNAs were significantly induced 1h after ionizing radiation (IR) in healthy donors, whereas none in AT patients. 447 mRNAs and 149 lncRNAs were induced 8h after IR in the control group, while only 100 mRNAs and 3 lncRNAs in AT patients. Among IR-induced mRNAs, we found several genes with well-known functions in DDR. Gene Set Enrichment Analysis and Gene Ontology revealed delayed induction of key DDR pathways in AT patients compared to controls. The induction and dynamics of selected 9 lncRNAs were confirmed by RT-qPCR at several time-points after IR on a larger cohort. Moreover, inhibition of ATM with a specific inhibitor (KU-60019) proved that those lncRNAs are dependent on ATM. Some of the detected lncRNAs are localized next to protein-coding genes involved in DDR. We observed that induction of lncRNAs after IR preceded changes in expression of adjacent genes. This indicates that IR-induced lncRNAs may regulate the transcription of nearby genes. Subcellular fractionation into chromatin, nuclear, and cytoplasmic fractions revealed that the majority of studied lncRNAs are localized in chromatin, which further suggests their role in regulation of gene expression. In summary, our study revealed several lncRNAs induced by IR in an ATM-dependent manner. Their co-localization and co-expression with genes involved in DDR suggest that those lncRNAs may be important players in cellular response to DNA damage.

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LncRNA and mRNA profiling in radiated mice bone marrow and hypothalamus pretreated with radioprotectants

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