Yohan Pierre Lefol

• Hubers, Lisa Anne; Skjetne, Alexander Myhr; Luna, Luisa; Lefol, Yohan Pierre; Lund, Solveig Osnes & Wågbø, Ane Marit [Show all 15 contributors for this article] (2026). Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics. Nucleic Acids Research (NAR). ISSN 0305-1048. 54(17). doi: 10.1093/nar/gkag876. Full text in Research Archive Show summary

  Nth like DNA glycosylase 1 (NTHL1), a key base excision repair enzyme, has long been considered essential for nuclear and mitochondrial genome integrity. Combining in vitro biochemical assays, in cellulo molecular biology, and bioinformatic analyses, we investigated how NTHL1 loss affects mitochondrial DNA (mtDNA) stability and mitochondrial function. Contrary to the conventional view that mtDNA damage is solely detrimental, we find that NTHL1 loss confers a beneficial, mitochondria-initiated phenotype in human cells. Despite accumulating mtDNA lesions, NTHL1 loss unexpectedly increases mtDNA copy number, elevates oxidative phosphorylation protein levels, and enhances mitochondrial respiration. NTHL1−/− cells also show increased mitochondrial mass and higher levels of the biogenesis regulator PGC1α and the fusion protein OPA1, indicating an adaptive response that boosts mitochondrial function and capacity. Consequently, NTHL1−/− cells exhibit resistance to mitochondrial stress, accompanied by increased eIF2α phosphorylation and reduced MYC levels, converging on a broader transcriptional adaptive program. This phenotype depends on mitochondrial NTHL1 and reactive oxygen species (ROS) signaling, since treatment with ROS scavengers or mitochondria-specific reintroduction of NTHL1 rescues it. Together, these findings position NTHL1 as a key modulator of mtDNA stability and mitochondrial function, revealing that loss of this DNA repair enzyme shifts cellular metabolism toward a stress-adaptive state and enhances resilience to oxidative stress.

• Suaste, Veronica; Presterud, Rebecca; Wennerström, Anna Berit; Wang, Heling; Zhang, Jianying & Lund, Solveig Osnes [Show all 16 contributors for this article] (2026). Transcriptional Profiling Shows Dampening of Interferon Gene Signatures by NAD Augmentation in Ataxia-Telangiectasia. International Journal of Molecular Sciences. ISSN 1661-6596. 27(13). doi: 10.3390/ijms27135652. Full text in Research Archive Show summary

  Ataxia-Telangiectasia (A-T) is a multisystem disorder caused by loss of A-T mutated (ATM) protein activity, characterized clinically by immunodeficiency and cerebellar ataxia. ATM is a master regulator of DNA damage responses and loss of ATM function is accompanied by persistent activation of PARP1 leading to depletion of intracellular NAD+ and dysfunction of a series of cellular signalling pathways dependent on NAD+, providing a mechanistic rationale for NAD+ augmentation therapy. We performed a clinical trial of NAD+ augmentation with nicotinamide riboside (NR) over 24 months in A-T patients where we observed improved coordination and eye movements in A-T patients. Here, by using peripheral blood mononuclear cells, we performed longitudinal transcriptome profiling to define molecular signatures of A-T and to assess pathway-level responses to NR supplementation. A-T patients exhibited reproducible transcriptomic alterations involving immune, vascular, and inflammatory pathways. NAD+ augmentation was associated with suppression of interferon response genes and modulation of networks correlated with neurological improvement. These findings establish systemic molecular signatures of A-T and identify potential blood-based biomarkers that reflect disease processes and therapeutic response, supporting the use of NAD+ augmentation as a disease-modifying strategy in A-T by dampening interferon signalling.

• Alsøe, Lene; Brackmann, Stephan Andreas; Liu, Yan; Wennerström, Anna Berit; Esbensen, Qin Ying & Kalyanasundaram, Sumana [Show all 10 contributors for this article] (2026). The Role of Nuclear APOBEC Enzymes in Neoplastic Progression of Ulcerative Colitis. Clinical and Experimental Gastroenterology. 19. doi: 10.2147/CEG.S588161. Full text in Research Archive Show summary

  Aberrant expression of the cytidine DNA deaminase AID in enterocytes within inflamed mucosa in ulcerative colitis (UC) patients has been proposed to be involved in progression of UC to colitis-associated colorectal cancer (CA-CRC). Here, we followed the expression of AID and other nuclear cytidine DNA deaminases of the APOBEC family through several stages of progression of UC in a CA-CRC case (UC progressor) and in a cohort of UC progressors and non-progressors. In inflamed and high-grade dysplastic mucosa, AICDA and APOBEC1 mRNAs, but not APOBEC3-family enzyme mRNAs, were overexpressed compared to non-inflamed tissue. Immunohistochemical staining did not show expression of AID or APOBEC3 enzymes in the enterocytes, neither in specimens from the CA-CRC case nor in biopsies from the progressor and non-progressor cohort. APOBEC1 was highly expressed in the enterocytes throughout the colorectum from the CA-CRC case and in most biopsies examined from the progressor and non-progressor cohort. The expression was not correlated with the histology of the mucosa or the progression status of the patients. In the CA-CRC case, we identified AID- and APOBEC3-associated mutation signatures in inflamed, high-grade dysplasia and cancer genomes. In conclusion, our findings suggest that AID or other nuclear APOBECs are unlikely to drive the progression of UC to CA-CRC late during course of UC. However, we cannot exclude the possibility that bursts of AID and nuclear APOBEC3 activity may contribute to formation of genome instability in early phases of disease development.

• Alsøe, Lene; Brackmann, Stephan Andreas; Lefol, Yohan Pierre; Wennerström, Anna Berit; Liu, Yan & Riques, Rosa Ana [Show all 8 contributors for this article] (2025). Colonic Mucosal Gene Expression Profile in Patients with Neoplastic Progression in Longstanding Ulcerative Colitis. Clinical and Experimental Gastroenterology. 18, p. 215–232. doi: 10.2147/ceg.s528854. Full text in Research Archive
• Bordin, Diana Lilian; Lefol, Yohan Pierre; Lagartos, Maria Jose Donate; Montaldo, Nicola Pietro; Rolseth, Veslemøy & Tekin, Nuriye Basdag [Show all 18 contributors for this article] (2025). SMUG1 DNA glycosylase modulates reward behaviour through regulation of olfactory receptor gene expression. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(14). doi: 10.1093/nar/gkaf722. Full text in Research Archive
• Lefol, Yohan Pierre; Hasle, Geir Amund; Hegre, Siv Anita; Samdal, Helle & Sætrom, Pål (2025). Using pseudotime derivative on single-cell RNA sequencing data to identify genes undergoing cell cycle regulation. Bioinformatics Advances. 5(1). doi: 10.1093/bioadv/vbaf123. Full text in Research Archive Show summary

  Motivation: The cell cycle is a critical part of cellular life, one that has long been studied, both directly, and through its regulatory components. Commonly, cell cycle synchronization or selection experiments are performed in order to study the cell cycle, thus chemically modifying the cells, or selecting them for specific phases. We seek to develop a means to study the cell cycle through the use of single cell RNA sequencing, effectively circumventing the need for such experiments. Results: We utilize a well-established pseudotime method, along with the predicted and real expression of genes to calculate the velocity of individual genes. We then utilize statistics and expected biological behaviour to identify genes with significant shifts in velocity within the pseudotime. Additionally, we show the ability to observe gene regulatory behaviour such as mRNA splicing and degradation rates. As many cell line based research utilize multiple replicates we implement a merger method for technical replicates to adjust for technical variations, creating a more robust analysis. In summary, our study develops a robust approach to map the velocities of individual, biologically, and statistically significant genes throughout the cell cycle’s phases within a cell line experiment

• Hubers, Lisa Anne; Skjetne, Alexander Myhr; Luna, Luisa; Lefol, Yohan Pierre; Lund, Solveig Osnes & Wågbø, Ane Marit [Show all 14 contributors for this article] (2024). Functional Impact of Nth-like DNA glycosylase on Mitochondrial Dynamics. bioRxiv. ISSN 2692-8205. doi: 10.1101/2024.10.10.617535. Full text in Research Archive Show summary

  ABSTRACT NTH-like DNA glycosylase (NTHL1), a key enzyme in the base excision repair (BER) pathway, has long been considered essential for maintaining both nuclear and mitochondrial genome integrity. In this study, we integrate in vitro biochemical assays, in-cellulo molecular biology experiments, and bioinformatic analyses to investigate the impact of NTHL1 loss on mitochondrial DNA (mtDNA) stability and function. Our findings challenge the conventional view by showing that the loss of NTHL1 confers a positive phenotype. Although NTHL1 deletion in human cells results in a significant accumulation of mtDNA lesions, it is unexpectedly accompanied by a substantial increase in mtDNA copy number (CN), which correlates with elevated oxidative phosphorylation (OXPHOS) protein levels and enhanced mitochondrial respiratory capacity. Additionally, NTHL1-knockout cells exhibit larger mitochondria and increased levels of the mitochondrial biogenesis regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and the membrane fusion protein Dynamin-like GTPase OPA1. These changes suggest an adaptive response to stress or altered cellular demands, aimed at enhancing mitochondrial function and capacity. Consequently, NTHL1 -knockout cells showed resistance to 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial stress along with increased phosphorylation of eIF2α. Together, this suggests that the loss of NTHL1 may enhance cellular resilience to oxidative stress by activating protective integrated stress response and mitohormesis pathways thereby contributing to cellular survival under adverse conditions. Collectively, our findings position NTHL1 as a key player in mtDNA stability and mitochondrial function, linking its DNA repair activity to the integrated stress response. Its loss triggers a shift from canonical oxidative phosphorylation to stress-adaptive pathways, ultimately enhancing cellular resistance against oxidative stress through the activation of the mitochondrial hormetic response.

• Kalyanasundaram, Sumana; Lefol, Yohan Pierre; Gundersen, Sveinung; Rognes, Torbjørn; Alsøe, Lene & Nilsen, Hilde [Show all 9 contributors for this article] (2023). hGSuite HyperBrowser: A web-based toolkit for hierarchical metadata-informed analysis of genomic tracks. PLOS ONE. 18(7). doi: 10.1371/journal.pone.0286330. Full text in Research Archive Show summary

  Many high-throughput sequencing datasets can be represented as objects with coordinates along a reference genome. Currently, biological investigations often involve a large number of such datasets, for example representing different cell types or epigenetic factors. Drawing overall conclusions from a large collection of results for individual datasets may be challenging and time-consuming. Meaningful interpretation often requires the results to be aggregated according to metadata that represents biological characteristics of interest. In this light, we here propose the hierarchical Genomic Suite HyperBrowser (hGSuite), an open-source extension to the GSuite HyperBrowser platform, which aims to provide a means for extracting key results from an aggregated collection of high-throughput DNA sequencing data. The hGSuite utilizes a metadata-informed data cube to calculate various statistics across the multiple dimensions of the datasets. With this work, we show that the hGSuite and its associated data cube methodology offers a quick and accessible way for exploratory analysis of large genomic datasets. The web-based toolkit named hGsuite Hyperbrowser is available at https://hyperbrowser.uio.no/hgsuite under a GPLv3 license.

• Prebensen, Christian Haugland; Lefol, Yohan Pierre; Myhre, Peder Langeland; Lüders, Torben; Jonassen, Christine M & Blomfeldt, Anita [Show all 9 contributors for this article] (2023). Longitudinal whole blood transcriptomic analysis characterizes neutrophil activation and interferon signaling in moderate and severe COVID-19. Scientific Reports. 13(1). doi: 10.1038/s41598-023-37606-y. Full text in Research Archive Show summary

  Abstract A maladaptive inflammatory response has been implicated in the pathogenesis of severe COVID-19. This study aimed to characterize the temporal dynamics of this response and investigate whether severe disease is associated with distinct gene expression patterns. We performed microarray analysis of serial whole blood RNA samples from 17 patients with severe COVID-19, 15 patients with moderate disease and 11 healthy controls. All study subjects were unvaccinated. We assessed whole blood gene expression patterns by differential gene expression analysis, gene set enrichment, two clustering methods and estimated relative leukocyte abundance using CIBERSORT. Neutrophils, platelets, cytokine signaling, and the coagulation system were activated in COVID-19, and this broad immune activation was more pronounced in severe vs. moderate disease. We observed two different trajectories of neutrophil-associated genes, indicating the emergence of a more immature neutrophil phenotype over time. Interferon-associated genes were strongly enriched in early COVID-19 before falling markedly, with modest severity-associated differences in trajectory. In conclusion, COVID-19 necessitating hospitalization is associated with a broad inflammatory response, which is more pronounced in severe disease. Our data suggest a progressively more immature circulating neutrophil phenotype over time. Interferon signaling is enriched in COVID-19 but does not seem to drive severe disease.

• Lefol, Yohan Pierre; Korfage, Tom; Mjelle, Robin; Prebensen, Christian Haugland; Lüders, Torben & Müller, Bruno [Show all 13 contributors for this article] (2023). TiSA: TimeSeriesAnalysis - A pipeline for the analysis of longitudinal transcriptomics data. NAR Genomics and Bioinformatics. 5(1). doi: 10.1093/nargab/lqad020. Full text in Research Archive Show summary

  Improved transcriptomic sequencing technologies now make it possible to perform longitudinal experiments, thus generating a large amount of data. Currently, there are no dedicated or comprehensive methods for the analysis of these experiments. In this article, we describe our TimeSeries Analysis pipeline (TiSA) which combines differential gene expression, clustering based on recursive thresholding, and a functional enrichment analysis. Differential gene expression is performed for both the temporal and conditional axes. Clustering is performed on the identified differentially expressed genes, with each cluster being evaluated using a functional enrichment analysis. We show that TiSA can be used to analyse longitudinal transcriptomic data from both microarrays and RNA-seq, as well as small, large, and/or datasets with missing data points. The tested datasets ranged in complexity, some originating from cell lines while another was from a longitudinal experiment of severity in COVID-19 patients. We have also included custom figures to aid with the biological interpretation of the data, these plots include Principal Component Analyses, Multi Dimensional Scaling plots, functional enrichment dotplots, trajectory plots, and complex heatmaps showing the broad overview of results. To date, TiSA is the first pipeline to provide an easy solution to the analysis of longitudinal transcriptomics experiments.

• Sengupta, Tanima; Lefol, Yohan Pierre; Lirussi, Lisa; Morales, Veronica Suaste; Lüders, Torben & Gupta, Swapnil [Show all 10 contributors for this article] (2022). Krill oil protects dopaminergic neurons from age-related degeneration through temporal transcriptome rewiring and suppression of several hallmarks of aging. Aging. 14(21), p. 8661–8687. doi: 10.18632/aging.204375. Full text in Research Archive Show summary

  There is accumulating evidence that interfering with the basic aging mechanisms can enhance healthy longevity. The interventional/therapeutic strategies targeting multiple aging hallmarks could be more effective than targeting one hallmark. While health-promoting qualities of marine oils have been extensively studied, the underlying molecular mechanisms are not fully understood. Lipid extracts from Antarctic krill are rich in long-chain omega-3 fatty acids choline, and astaxanthin. Here, we used C. elegans and human cells to investigate whether krill oil promotes healthy aging. In a C. elegans model of Parkinson´s disease, we show that krill oil protects dopaminergic neurons from aging-related degeneration, decreases alpha-synuclein aggregation, and improves dopamine-dependent behavior and cognition. Krill oil rewires distinct gene expression programs that contribute to attenuating several aging hallmarks, including oxidative stress, proteotoxic stress, senescence, genomic instability, and mitochondrial dysfunction. Mechanistically, krill oil increases neuronal resilience through temporal transcriptome rewiring to promote anti-oxidative stress and anti-inflammation via healthspan regulating transcription factors such as SNK-1. Moreover, krill oil promotes dopaminergic neuron survival through regulation of synaptic transmission and neuronal functions via PBO-2 and RIM-1. Collectively, krill oil rewires global gene expression programs and promotes healthy aging via abrogating multiple aging hallmarks, suggesting directions for further pre-clinical and clinical explorations.

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• Prebensen, Christian Haugland; Lefol, Yohan Pierre; Myhre, Peder Langeland; Lüders, Torben; Jonassen, Christine M & Blomfeldt, Anita [Show all 9 contributors for this article] (2023). Author Correction: Longitudinal whole blood transcriptomic analysis characterizes neutrophil activation and interferon signaling in moderate and severe COVID-19 (Scientific Reports, (2023), 13, 1, (10368), 10.1038/s41598-023-37606-y). Scientific Reports. 13(1). doi: 10.1038/s41598-023-39872-2. Full text in Research Archive

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