Biology subjects

Zahnreich, S.

Publications and source records attributed to Zahnreich, S..

5 recordsLinked to original sources

bioRxiv2026

Comparative Transcriptional Responses of Human Blood to Neutron and Photon Irradiation

Despite the well-known health risks of neutron exposures, key gaps remain in understanding neutron-induced molecular responses and identifying reliable biodosimetric markers that distinguish neutrons from photon exposure. We provide the first genome-wide analysis of the human blood transcriptional response to an accelerator-derived fission-like spectrum of neutrons versus photons, evaluating transcriptomic relative biological effectiveness (RBE) and radiation quality-discriminating gene signatures. Whole blood from healthy donors was irradiated ex vivo with X-rays (140 kV, 0-4 Gy, n = 3) or neutrons (0.1-8 MeV, 0-1 Gy, n = 2), incubated for 6 h or 24 h, and processed for RNA sequencing from peripheral blood mononuclear cells (PBMCs). Neutrons were markedly more potent than X-rays at inducing differentially expressed genes (DEGs) at equal doses, showing a peak response 6 h post-irradiation followed by a decline. In contrast, X-rays caused a continuous increase in DEGs up to 24 h (neutrons vs. X-rays at 1 Gy: 1,449 vs. 121 DEGs at 6 h; 996 vs. 621 DEGs at 24 h). A universal p53-centered 34-gene signature, including FDXR, EDA2R, GADD45A, and ZMAT3, showed highly monotonic dose responses (Spearman correlation coefficient {approx} 1) across donors, radiation qualities, and timepoints. Additionally, difference-in-differences analysis identified radiation quality-discriminating genes only at 6 h, with transcriptional convergence observed by 24 h, suggesting a very narrow time window for biodosimetric differentiation. We identified a neutron-specific gene signature driven by cGAS-STING-NF-{kappa}B signaling (RELB, NFKB1, C3, MALAT1) and suppression of B-cell and myeloid identity genes (IGHD, TCL1A, CLEC7A, TLR2), defining a biologically coherent neutron quality index with distinct immunomodulatory effects. For the first time, we assessed neutron RBEs at the gene, pathway, and global transcriptomic levels in a human blood model, reporting a global transcriptomic neutron RBE of 1.30 (95% CI: 1.14-1.49) at 6 h and 1.21 (95% CI: 1.14-1.28) at 24 h, providing a valuable basis for biodosimetry in mixed-field exposure scenarios. Our findings advance the mechanistic understanding of neutron radiation responses and support the development of biodosimetric approaches for mixed-field exposure scenarios.

biophysics↗

bioRxiv2026

Decoding Radiation-Induced Transcriptomic Signatures of Whole Blood Using Long-Read RNA-Seq: Clinical and Biodosimetric Implications

Background: Gene expression profiling in radiation-exposed blood is a valuable tool for biodosimetry and clinical research. Evaluating the blood's transcriptomic radiation response provides insight into absorbed dose, hematotoxicities, and immune reactions. However, detailed analysis using long-read RNA sequencing is currently limited in its diffusion, despite the potential additional insights that could be extracted, including novel isoform discovery and on-the-field gene expression studies, owing to its portability. Results: In this study, we utilized Oxford Nanopore Technologies' long-read RNA sequencing on human peripheral blood leukocytes from three healthy donors 6 hours after exposure of whole peripheral blood to 4 Gy of X-rays. Compared to sham-irradiated (0 Gy) blood samples, gene-level differential expression analysis identified 117 upregulated and 66 downregulated genes, including canonical DNA damage repair and inflammatory responses. At the transcript level, 102 transcripts were significantly upregulated, and 17 were downregulated, revealing isoform-specific regulation that was not captured at the gene level. Notably, IL32, which was not detected as significantly changed at the gene level, exhibited significant upregulation of two transcript isoforms (log2 fold-changes of 1.19 and 1.99), while WDR74, ITM2B, AK2, and RPS19 displayed changes in transcript usage following irradiation. Leveraging long-read RNA sequencing, we further identified novel candidate isoforms, including protein-coding isoforms of PHPT1 and FBXO22 as well as non-coding candidates. Notably, the FBXO22 isoform showed evidence of altered protein domain architecture relative to the reference isoform. Conclusions: This study is the first to systematically investigate differential transcript usage in the leukocyte fraction of irradiated human whole blood using long-read RNA sequencing. We confirmed known radiation-response signatures at the gene level and identified isoform-level transcriptomic changes, including several isoforms that were undetectable in our previously generated matched short-read dataset. These findings demonstrate the potential of long-read RNA sequencing to provide a more detailed view of radiation-induced transcriptomic alterations, with potential applications in biodosimetry and clinical settings.

biophysics↗

bioRxiv2025

Repair of DNA double-strand breaks after low radiation doses in childhood cancer survivors and matched cancer-free individuals

DNA double-strand breaks (DSBs) which arise in G1- or G0-phase normal human cells are repaired by non-homologous end-joining (NHEJ), a pathway which is important for cell survival but can cause mutations at the break sites. DSB repair by NHEJ is very efficient at high damage levels of 1 or more DSBs per cell, much less efficient at lower damage levels and almost absent if only [~]0.05 DSBs per cell are induced. Repair at this low DSB level can be induced if cells are pre-treated prior to DSB induction with low concentrations of hydrogen peroxide, suggesting that the intracellular radical level modulates the efficiency of DSB repair at low damage levels. Here, we have investigated if the inefficiency of repair at low DSB levels contributes to the carcinogenic potential of DSBs or, counterintuitively, may serve as a mechanism to limit cancer development. We have analyzed the repair of high and low levels of radiation-induced DSBs in primary fibroblasts from 136 childhood cancer survivors, half of whom developed a second independent tumor later in life, and compared it to the response of primary fibroblasts from 68 individually matched cancer-free individuals. Although childhood cancer survivors and cancer-free individuals repaired DSBs at high damage levels equally efficiently, their response to low DSB levels differed drastically. While repair in cancer-free individuals was nearly absent at a level of [~]0.05 DSBs per cell, childhood cancer survivors repaired DSBs at this low damage level as efficiently as after high damage levels. These results suggest that most of the cancer survivors analyzed here carry a genetic predisposition that affects their response to low levels of DSBs. They also support the idea that the absence of repair observed in cancer-free individuals represents a mechanism limiting cancer formation.

cell biology↗

bioRxiv2025

DoReMiTra: An R/Bioconductor data package for orchestrating the analysis of radiation transcriptomic studies

SummaryUnderstanding the molecular impact of ionizing radiation exposure is essential for both biomedical research and public health. Among the possible approaches to study this phenomenon, gene expression profiling via transcriptomics assays has been a valuable approach over the last decades to unravel the mechanisms of cellular responses to radiation. To our knowledge, there is no data package gathering well-curated radiation transcriptomic datasets covering microarrays and, more recently, RNA sequencing. Therefore, we present DoReMiTra, an R/Bioconductor data package that represents the first unified radiation transcriptomics dataset collection integrated with Bioconductors ExperimentHub for efficient distribution. DoReMiTra standardizes and harmonizes sample-level metadata and provides pre-processed SummarizedExperiment (SE) objects to facilitate comparative analyses. Additionally, we introduce a lightweight Shiny app interface for interactive visualization and preliminary exploration. DoReMiTra serves as a valuable resource and tool in radiation research for benchmarking, integrative analyses, and biomarker discovery. Availability and ImplementationDoReMiTra is available under the MIT license at https://bioconductor.org/packages/DoReMiTra.

bioinformatics↗

bioRxiv2025

Genome-wide transcriptomic response of whole blood to radiation

The hematological system is impacted in nearly all ionizing radiation exposure scenarios. Whole transcriptome data offer detailed insights into bloods radiation response, crucial for radiotherapy and biodosimetry. We conducted genome-wide RNA-seq analysis on blood from three donors irradiated ex vivo with X-rays and incubated for 2h and 6h. Gene expression was subject to strong inter-donor variation and time post-exposure. After 0.5, 1, 2, and 4 Gy X-rays, 5, 33, 84, and 364 genes (2h) and 72, 99, 274, and 607 genes (6h) were differentially expressed (DEG), compared to 0 Gy. The corresponding number of the inferred transcription factors was 255, 253, 274, and 292 after 2h and 214, 245, 262, and 279 after 6h. In sham-irradiated blood, 924 DEGs and 165 transcription factors were affected by ex vivo incubation alone. We identified 34 radioresponsive DEGs not previously described, 8 and 9 showing significant positive or negative correlations with dose, respectively, including GPN1, MRM2, G0S2, and PTPRS. DNA damage signaling pathways were affected from the lowest dose, with doses [≥] 2 Gy additionally triggering proinflammatory responses. This first genome-wide RNA-seq study of ex vivo X-ray-exposed human blood reveals novel radiosensitive genes, transcription factors, and pathways, enhancing the understanding of the consequences of diagnostic, therapeutic, or accidental exposures on the highly radioresponsive hematological system.

biophysics↗