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Transcriptome Sequencing Analysis (RNA-Seq) of Bone Marrow Hematopoietic Stem Cells from Per2-mutant Mice

ABSTRACT: Circadian rhythm (CR) and environmental low-dose radiation (LDR) evident on Earth’s surface may have coordinated in the evolution of early life; disturbed CR and/or overexposure to radiation are linked with aging and many human diseases including cancer. Although CR affects tumor response and normal tissue radiosensitivity in cancer radiotherapy, it is unclear how CR proteins function in LDR induced radioprotection. Herein, we demonstrated that mice carrying a deficient Period2 gene (C57BL-Per2 def ), a core CR regulator, were highly sensitive to radiation. Compared to Per2 wt mice, the population of bone marrow hemopoietic stem cells (BMHSCs) was reduced and a cluster of genes responsible for DNA damage repair and mitochondrial metabolism was silenced in the Per2 def BMHSCs . Consistently, unlike Per2 wt human and mouse cells capable of inducible radioresistance by LDR, Per2 def cells failed to induce such adaptive protection. Furthermore, LDR enhanced PER2 protein level together with phosphorylated GSK3β (pGSK3β) in the Wnt/β-catenin signaling pathway. Interaction of PER2 with pGSK3β activated β -catenin that in turn transactivated Per2 and other prosurvival genes. These results provide new insights into how CR and LDR communicate in genotoxic stress response. The PER2/pGSK3β/β-catenin/Per2 pathway may serve as a therapeutic approach to reduce normal cell injury in cancer radiotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE184407 | GEO | 2022/11/04

REPOSITORIES: GEO

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Project description:Although radiation effects have been extensively studied, the biological effects of low-dose radiation (LDR) are controversial. This study investigates LDR-induced alterations in locomotive behavior and gene expression profiles of Drosophila melanogaster. We measured locomotive behavior using larval pupation height and rapid iterative negative geotaxis (RING) assay after exposure to 0.1 Gy gamma-radiation (dose rate of 16.7 mGy/h). We also observed chronic LDR effects on development (pupation and eclosion rates) and longevity (life span). To identify chronic LDR effects on gene expression, we performed whole-genome expression analysis using gene-expression microarrays, and confirmed the results using quantitative real-time PCR. Pupation height was significantly higher after LDR treatment at the first larval instar. Locomotive behavior of male flies was significantly greater approximately 3M-BM--5 weeks after LDR, but pupation and eclosion rates and life spans were not significantly different. Genome-wide expression analysis identified 344 genes that were differentially expressed in irradiated larvae compared with those of controls. We identified several genes belonging to larval behavior functional groups such as locomotive behavior and oxidation reduction, and genes involved in conventional functional groups modulated by irradiation such as defense response, sensory and perception. Four candidate genes were confirmed as differentially expressed genes in irradiated larvae using qRT-PCR. These data suggest that LDR stimulates locomotion-related genes, and these genes can be used as potential markers for LDR. Eggs were collected from 5-day-old female flies and cultivated for 24 h on standard medium. Then, twenty larvae were manually selected and seeded on fresh standard medium in a new vial. After transfer, the experimental group of first-instar larvae was immediately irradiated with chronic gamma-radiation at a dose rate of 16.7 mGy/h. After treatment, gamma-irradiated flies and non-irradiated control flies were maintained in the same incubator at 25degC.

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Transcriptome Sequencing Analysis (RNA-Seq) of Bone Marrow Hematopoietic Stem Cells from Per2-mutant Mice

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