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Dose dependent transcriptional response to ionizing radiation is orchestrated with DNA repair within the nuclear space [RNA-seq]

ABSTRACT: Radiation therapy is commonly used to treat glioblastoma multiforme (GBM) brain tumor. Ionizing radiation (IR) induces dose- specific variations in transcriptional programs, implicating they are tightly regulated and critical components in the tumor response and survival. Yet, our understanding of the downstream molecular events triggered by lethal vs sublethal IR doses is limited. Herein, we report that variations in the genetic programs are positively and functionally correlated with the exposure to lethal or sublethal IR doses. Genome architecture analysis revealed that gene regulation is spatially and temporally coordinated with DNA repair kinetics. Radiation-activated genes were pre-positioned in active sub-nuclear compartments and were up-regulated following DNA damage response, while the DNA repair activity shifted to the inactive heterochromatic spatial compartments. The IR dose affected the levels of DNA damage repair and transcription modulation, but not the order of events, which was linked to their spatial nuclear positioning. Thus, distinct coordinated temporal dynamics of DNA damage repair and transcription reprogramming in the active and inactive sub-nuclear compartments highlight the importance of high-order genome organization in synchronizing the molecular events following IR.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244666 | GEO | 2024/01/29

REPOSITORIES: GEO

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Project description:Increased use of nuclear reactors and radioactive materials for energy production and proliferation of nuclear weaponry increases risk of radiation exposure or nuclear accidents. Development of radiation countermeasures for the diagnosis, prognosis, and radiation treatment are trailing behind, and knowledge of the deleterious radiation effects on health and responses to exposure at the molecular, cellular, and systems biology level are still not fully understood. In this work, skin biopsies collected at h2, d4, d7, d21, and d28 from mice exposed to 1, 3, 6, 20Gy of whole-body x-ray ionizing radiation were used in a transcriptomic approach to evaluate the potential of radiation-induced transcriptional alterations in diagnosis and prognosis of a radiation event. Mice exposed to 20Gy were euthanized under the humane endpoint of an IACUC approved study protocol at d7 while mice that received 1, 3, 6Gy survived the full 28 days time course. Sammon plot analysis showed a clear separation of samples based on survival and timepoints within lethal (20Gy) and in the sublethal (1, 3, 6Gy) IR doses. Differences in the numbers, regulation mode, and fold change of significantly differentially transcribed genes (SDTGs, p < 0.05 and FC > 2) were identified between lethal and sublethal doses. Down and upregulation dominated transcriptomes during the first post-exposure week, respectively. Numbers of SDTGs and percentages of upregulated SDTGs revealed stationary transcription and low upregulation percentages after lethal dose in contrary to transcription responses that were dynamic and largely upregulated after exposure to sublethal doses. Longitudinal variations in numbers of up/downregulated SDTGs suggested delayed and extended responses with increasing IR doses in the sublethal range with lethal-like responses in late time points suggesting more than a single-phase response. This was supported further by the distributions of common and unique genes across the TPs within each dose. Several genes with potential use as markers for radiation exposure and dosimetric applications were identified. Pathways enrichment analysis showed strong modulations of immune responses, fibrosis development, detoxification responses, hematological responses, skin reactions, neurological system disruptions, maintenance of gastric mucosa, and cell survival, migration, and proliferation pathways. The majority of the identified pathways were predicted activated after sublethal and inactivated after lethal exposures, particularly during the first post-exposure week.

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Dose dependent transcriptional response to ionizing radiation is orchestrated with DNA repair within the nuclear space [RNA-seq]

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