'; ?> geneimprint : Hot off the Press http://www.geneimprint.com/site/hot-off-the-press Daily listing of the most recent articles in epigenetics and imprinting, collected from the PubMed database. en-us Fri, 13 Dec 2024 06:25:02 EST Fri, 13 Dec 2024 06:25:02 EST jirtle@radonc.duke.edu james001@jirtle.com Multi Layered Omics Approaches Reveal Glia Specific Alterations in Alzheimer's Disease: A Systematic Review and Future Prospects. İş Ã–, Min Y, Wang X, Oatman SR, Abraham Daniel A, Ertekin-Taner N
Glia (Dec 2024)

Alzheimer's disease (AD) is the most common neurodegenerative dementia with multi-layered complexity in its molecular etiology. Multiple omics-based approaches, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics are enabling researchers to dissect this molecular complexity, and to uncover a plethora of alterations yielding insights into the pathophysiology of this disease. These approaches reveal multi-omics alterations essentially in all cell types of the brain, including glia. In this systematic review, we screen the literature for human studies implementing any omics approach within the last 10 years, to discover AD-associated molecular perturbations in brain glial cells. The findings from over 200 AD-related studies are reviewed under four different glial cell categories: microglia, oligodendrocytes, astrocytes and brain vascular cells. Under each category, we summarize the shared and unique molecular alterations identified in glial cells through complementary omics approaches. We discuss the implications of these findings for the development, progression and ultimately treatment of this complex disease as well as directions for future omics studies in glia cells.]]> Wed, 31 Dec 1969 19:00:00 EST Metabolomics for enhanced clinical understanding of inflammatory bowel disease. Boye TL, Hammerhøj A, Nielsen OH, Wang Y
Life Sci (Dec 2024)

Metabolomics is an emerging field involving the systematic identification and quantification of numerous metabolites in biological samples. Precision medicine applies multiomics systems biology to individual patients for reliable diagnostic classification, disease monitoring, and treatment. Multiomics systems biology encompasses genomics, transcriptomics, proteomics, epigenomics, and metabolomics. Therefore, metabolomic techniques could be highly valuable for future clinical decision-making. This review provides a technical overview of two commonly used techniques for metabolomics measurements: mass spectrometry (MS) and proton nuclear magnetic resonance (H NMR) spectroscopy. We also discuss recent clinical advances in these techniques. Individuals with inflammatory bowel disease (IBD) exhibit significant variability in prognosis and response to treatment. Since both genetic predisposition and environmental factors contribute to this condition, targeting the metabolome may provide key insights for distinguishing and profiling patients with different clinical needs. Additionally, the considerable overlap in the clinical presentation of various disease subtypes emphasizes the need for enhanced diagnostic methods to improve patient care.]]> Wed, 31 Dec 1969 19:00:00 EST Using Callus as an Ex Vivo System for Chromatin Analysis. Lavie O, Williams LE
Methods Mol Biol (2025)

Next-generation sequencing has revolutionized epigenetics research, enabling a comprehensive analysis of DNA methylation and histone modification profiles to explore complex biological systems at unprecedented depth. Deciphering the intricate epigenetic mechanisms that regulate gene activity presents significant challenges, including the issue of analyzing heterogeneous cell populations in bulk. Bulk analysis introduces bias and can obscure crucial information by averaging readouts from distinct cells. Various approaches have been developed to address this issue, such as cell-type-specific enrichment or single-cell sequencing techniques. However, the need for transgenic lines with fluorescent markers, along with technical challenges such as efficient protoplast isolation and low yield, limits their widespread adoption and use in multi-omic studies. This review discusses the pros and cons of these approaches, providing a valuable basis for selecting the most suitable strategy to minimize heterogeneity. We will also highlight the use of cotyledon-derived callus as an ex vivo system as a simple, accessible, and robust platform for enabling high-throughput multi-omic analyses.]]> Wed, 31 Dec 1969 19:00:00 EST Emergent properties of the lysine methylome reveal regulatory roles via protein interactions and histone mimicry. Pollin G, Chi YI, Mathison AJ, Zimmermann MT, Lomberk G, Urrutia R
Epigenomics (Dec 2024)

Epigenomics has significantly advanced through the incorporation of Systems Biology approaches. This study aims to investigate the human lysine methylome as a system, using a data-science approach to reveal its emergent properties, particularly focusing on histone mimicry and the broader implications of lysine methylation across the proteome.]]> Wed, 31 Dec 1969 19:00:00 EST HiChIP for Plant Tissues. Brik Chaouche R, Raynaud C, Benhamed M, Latrasse D
Methods Mol Biol (2025)

While most epigenomics studies are based on a linear view of genome organization, the necessity to take the three-dimensional chromatin folding into account to understand transcriptional regulation is now clearly recognized. In the past years, approaches combining proximity-based ligation with high-throughput sequencing have opened the way to study long/short-range chromatin interactions and, thus, to analyze 3D chromatin organization. Among them, HiChIP, a protein-based method to capture chromatin interactions, gave rise to the most comprehensive view of the chromatin contacts involving specific chromatin components in a given system. Here, we describe a detailed procedure to produce HiChIP libraries starting from plant tissues.]]> Wed, 31 Dec 1969 19:00:00 EST Integration of multi-omics layers empowers precision diagnosis through unveiling pathogenic mechanisms on maple syrup urine disease. Tejedor JR, Soriano-Sexto A, Beccari L, Castejón-Fernández N, Correcher P, Sainz-Ledo L, Alba-Linares JJ, Urdinguio RG, Ugarte M, Fernández AF, Rodríguez-Pombo P, Fraga MF, Pérez B
J Inherit Metab Dis (Dec 2024)

Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by deficient activity of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, required to metabolize the amino acids leucine, isoleucine, and valine. Despite its profound metabolic implications, the molecular alterations underlying this metabolic impairment had not yet been completely elucidated. We performed a comprehensive multi-omics integration analysis, including genomic, epigenomic, and transcriptomic data from fibroblasts derived from a cohort of MSUD patients and unaffected controls to genetically characterize an MSUD case and to unravel the MSUD pathophysiology. MSUD patients exhibit a defined episignature that reshapes the global DNA methylation landscape, resulting in the stimulation of HOX cluster genes and the restriction of cell cycle gene-related signatures. Subsequent data integration revealed the impact of AP1-related and CEBPB transcription factors on the observed molecular reorganization, with MEIS1 emerging as a potential downstream candidate affected by robust epigenetic repression in MSUD patients. Furthermore, the integration of multi-omics layers facilitated the identification of a strong epigenetic repression in the DBT promoter in a patient wherein no BCKDH pathogenic variants had been detected. A Circular Chromatin Conformation Capture assay indicated a disturbance of the interactions of DBT promoter, thereby unveiling alternative modes of disease inheritance. Integration of multi-omics data unveiled underlying molecular networks rewired in MSUD patients and represents a powerful approach with diagnostic potential for rare genetic disorders with unknown genetic bases.]]> Wed, 31 Dec 1969 19:00:00 EST Research progress and the prospect of using single-cell sequencing technology to explore the characteristics of the tumor microenvironment. Zhang W, Zhang X, Teng F, Yang Q, Wang J, Sun B, Liu J, Zhang J, Sun X, Zhao H, Xie Y, Liao K, Wang X
Genes Dis (Jan 2025)

In precision cancer therapy, addressing intra-tumor heterogeneity poses a significant obstacle. Due to the heterogeneity of each cell subtype and between cells within the tumor, the sensitivity and resistance of different patients to targeted drugs, chemotherapy, , are inconsistent. Concerning a specific tumor type, many feasible treatments or combinations can be used by specifically targeting the tumor microenvironment. To solve this problem, it is necessary to further study the tumor microenvironment. Single-cell sequencing techniques can dissect distinct tumor cell populations by isolating cells and using statistical computational methods. This technology may assist in the selection of targeted combination therapy, and the obtained cell subset information is crucial for the rational application of targeted therapy. In this review, we summarized the research and application advances of single-cell sequencing technology in the tumor microenvironment, including the most commonly used single-cell genomic and transcriptomic sequencing, and their future development direction was proposed. The application of single-cell sequencing technology has been expanded to include epigenomics, proteomics, metabolomics, and microbiome analysis. The integration of these different omics approaches has significantly advanced the development of single-cell multiomics sequencing technology. This innovative approach holds immense potential for various fields, such as biological research and medical investigations. Finally, we discussed the advantages and disadvantages of using single-cell sequencing to explore the tumor microenvironment.]]> Wed, 31 Dec 1969 19:00:00 EST X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes. Hasenbein TP, Hoelzl S, Smith ZD, Gerhardinger C, Gonner MOC, Aguilar-Pimentel A, Amarie OV, Becker L, Calzada-Wack J, Dragano NRV, da Silva-Buttkus P, Garrett L, Hölter SM, Kraiger M, Östereicher MA, Rathkolb B, Sanz-Moreno A, Spielmann N, Wurst W, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Meissner A, Engelhardt S, Rinn JL, Andergassen D
Nat Commun (Dec 2024)

The lncRNA Crossfirre was identified as an imprinted X-linked gene, and is transcribed antisense to the trans-acting lncRNA Firre. The Firre locus forms an inactive-X-specific interaction with Dxz4, both loci providing the platform for the largest conserved chromatin structures. Here, we characterize the epigenetic profile of these loci, revealing them as the most female-specific accessible regions genome-wide. To address their in vivo role, we perform one of the largest X-linked knockout studies by deleting Crossfirre, Firre, and Dxz4 individually and in combination. Despite their distinct epigenetic features observed on the X chromosome, our allele-specific analysis uncovers these loci as dispensable for imprinted and random X chromosome inactivation. However, we provide evidence that Crossfirre affects autosomal gene regulation but only in combination with Firre. To shed light on the functional role of these sex-specific loci, we perform an extensive standardized phenotyping pipeline and uncover diverse knockout and sex-specific phenotypes. Collectively, our study provides the foundation for exploring the intricate interplay of conserved X-linked loci in vivo.]]> Wed, 31 Dec 1969 19:00:00 EST ChIPmentation for Epigenomic Analysis in Fission Yeast. Dewornu FS, Tong P, Torres-Garcia S, Pidoux A, Allshire R, Shukla M
Methods Mol Biol (2025)

Histone modifications and transcription factor-DNA interactions regulate vital processes such as transcription, recombination, repair, and accurate chromosome segregation. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been instrumental in studying genome-wide distribution of DNA-bound or chromatin-associated factors and histone posttranslational modifications (PTMs). Here, we describe a ChIPmentation protocol adapted for fission yeast, Schizosaccharomyces pombe. This method merges Tn5 mediated tagmentation with existing ChIP protocols, resulting in lower sample input requirements with significant reduction in hands-on time and sample preparation costs.]]> Wed, 31 Dec 1969 19:00:00 EST Clinical utility of regions of homozygosity (ROH) identified in exome sequencing: when to pursue confirmatory uniparental disomy testing for imprinting disorders? Huo X, Lu X, Lu D, Liu H, Liu Y, Zhao Q, Sun Y, Dai W, Qiu W, Yu Y, Fan Y
Clin Chem Lab Med (Jan 2025)

Regions of homozygosity (ROH) could implicate uniparental disomy (UPD) on specific chromosomes associated with imprinting disorders. Though the algorithms for ROH detection in exome sequencing (ES) have been developed, optimal reporting thresholds and when to pursue confirmatory UPD testing for imprinting disorders remain in ambiguity. This study used a data-driven approach to assess optimal reporting thresholds of ROH in clinical practice.]]> Wed, 31 Dec 1969 19:00:00 EST Exploring the use of immunomethylomics in the characterization of depressed patients: A proof-of-concept study. Van Assche E, Hohoff C, Su Atil E, Wissing SM, Serretti A, Fabbri C, Pisanu C, Squassina A, Minelli A,  , Baune BT
Brain Behav Immun (Jan 2025)

Alterations in DNA methylation and inflammation could represent valid biomarkers for the stratification of patients with major depressive disorder (MDD). This study explored the use of DNA-methylation based immunological cell-type profiles in the context of MDD and symptom severity over time. In 119 individuals with MDD, DNA-methylation was assessed on whole blood using the Illumina Infinium MethylationEPIC 850 k BeadChip. Quality control and data processing, as well as cell type estimation was conducted using the RnBeads package. The cell type composition was estimated using epigenome-wide DNA methylation signatures, applying the Houseman method, considering six cell types (neutrophils, natural killer cells (NK), B cells, CD4+ T cells, CD8+ T cells and monocytes). Two cytokines (IL-6 and IL-1β) and hsCRP were quantified in serum. We performed a hierarchical cluster analysis on the six estimated cell-types and tested the differences between these clusters in relation to the two cytokines and hsCRP, depression severity at baseline, and after 6 weeks of treatment (celecoxib/placebo + vortioxetine). We performed a second cluster analysis with cell-types and cytokines combined. ANCOVA was used to test for differences across clusters. We applied the Bonferroni correction. After quality control, we included 113 participants. Two clusters were identified, cluster 1 was high in CD4+ cells and NK, cluster 2 was high in CD8+ T-cells and B-cells, with similar fractions of neutrophils and monocytes. The clusters were not associated with either of the two cytokines and hsCRP, or depression severity at baseline, but cluster 1 showed higher depression severity after 6 weeks, corrected for baseline (p = 0.0060). The second cluster analysis found similar results: cluster 1 was low in CD8+ T-cells, B-cells, and IL-1β. Cluster 2 was low in CD4+ cells and natural killer cells. Neutrophils, monocytes, IL-6 and hsCRP were not different between the clusters. Participants in cluster 1 showed higher depression severity at baseline than cluster 2 (p = 0.034), but no difference in depression severity after 6 weeks. DNA-methylation based cell-type profiles may be valuable in the immunological characterization and stratification of patients with MDD. Future models should consider the inclusion of more cell-types and cytokines for better a prediction of treatment outcomes.]]> Wed, 31 Dec 1969 19:00:00 EST Omics Approaches to Investigate the Pathogenesis of Suicide. Boldrini M, Xiao Y, Singh T, Zhu C, Jabbi M, Pantazopoulos H, Gürsoy G, Martinowich K, Punzi G, Vallender EJ, Zody M, Berretta S, Hyde TM, Kleinman JE, Marenco S, Roussos P, Lewis DA, Turecki G, Lehner T, Mann JJ
Biol Psychiatry (Dec 2024)

Suicide is the second leading cause of death in U.S. adolescents and young adults and is generally associated with a psychiatric disorder. Suicidal behavior has a complex etiology and pathogenesis. Moderate heritability suggests genetic causes. Associations between childhood and recent life adversity indicate contributions from epigenetic factors. Genomic contributions to suicide pathogenesis remain largely unknown. This article is based on a workshop held to design strategies to identify molecular drivers of suicide neurobiology that would be putative new treatment targets. The panel determined that while bulk tissue studies provide comprehensive information, single-nucleus approaches that identify cell type-specific changes are needed. While single-nuclei techniques lack information on cytoplasm, processes, spines, and synapses, spatial multiomic technologies on intact tissue detect cell alterations specific to brain tissue layers and subregions. Because suicide has genetic and environmental drivers, multiomic approaches that combine cell type-specific epigenome, transcriptome, and proteome provide a more complete picture of pathogenesis. To determine the direction of effect of suicide risk gene variants on RNA and protein expression and how these interact with epigenetic marks, single-nuclei and spatial multiomics quantitative trait loci maps should be integrated with whole-genome sequencing and genome-wide association databases. The workshop concluded with a recommendation for the formation of an international suicide biology consortium that will bring together brain banks and investigators with expertise in cutting-edge omics technologies to delineate the biology of suicide and identify novel potential treatment targets to be tested in cellular and animal models for drug and biomarker discovery to guide suicide prevention.]]> Wed, 31 Dec 1969 19:00:00 EST Extracting Chromosome Structural Information as One-Dimensional Metrics and Integrating Them with Epigenomics. Wang J, Chen H
Methods Mol Biol (2025)

Hi-C is a powerful method for obtaining genome-wide chromosomal structural information. The typical Hi-C analysis utilizes a two-dimensional (2D) contact matrix, which poses challenges for quantitative comparisons, visualizations, and integrations across multiple datasets. Here, we present a protocol for extracting one-dimensional (1D) features from chromosome structure data by HiC1Dmetrics. Leveraging these 1D features enables integrated analysis of Hi-C and epigenomic data.]]> Wed, 31 Dec 1969 19:00:00 EST BASAL: a universal mapping algorithm for nucleotide base-conversion sequencing. Xu M, Liu X, Wang M, Luo T, Gao Y, Liu J, Shi J
Nucleic Acids Res (Dec 2024)

Utilizing base-conversion (BC) techniques, single-base resolution profiling of RNA and DNA modifications has significantly advanced. BC strategies range from one-way conversions (e.g. cytosine-to-thymine for 5-methylcytosine, adenine-to-guanine for N6-methyladenosine), to multi-way conversions (e.g. adenine to cytosine/guanine/thymine for N1-methyladenosine) and deletion-induced conversions (e.g. pseudouridine-to-deletion). Existing sequence aligners struggle with these diverse conversions, often leading to misaligning or inefficiency. We introduce BASAL (BAse-conversion Sequencing ALigner), which leverages bit-masking technology to accurately calculate mismatch penalties and supports all BC strategies. BASAL outperforms state-of-the-art tools in both mapping accuracy and efficiency. Through simulated and real data testing, along with experimental validation, we demonstrate that BASAL excels at identifying reliable modification sites. Moreover, BASAL enhances single-cell m6A analysis, revealing cell subpopulations and a cell evolutionary direction that align with biological functions, which other aligners fall short. BASAL's versatility establishes it as a universal aligner for RNA and DNA modification sequencing, facilitating groundbreaking discoveries in epigenomics and epitranscriptomics.]]> Wed, 31 Dec 1969 19:00:00 EST Learning Enhancer-Gene associations from Bulk Transcriptomic and Epigenetic Sequencing Data with STITCHIT. Rumpf L, Schulz MH
Methods Mol Biol (2025)

To reveal gene regulation mechanisms, it is essential to understand the role of regulatory elements, which are possibly distant from gene promoters. Integrative analysis of epigenetic and transcriptomic data can be used to gain insights into gene-expression regulation in specific phenotypes. Here, we discuss STITCHIT, an approach to dissect epigenetic variation in a gene-specific manner across many samples for the identification of regulatory elements without relying on peak calling algorithms. The obtained genomic regions are then further refined using a regularized linear model approach, which can also be used to predict gene expression. We illustrate the use of STITCHIT using H3k27ac ChIP-seq and RNA-seq data from the International Human Epigenome Consortium (IHEC).]]> Wed, 31 Dec 1969 19:00:00 EST Therapeutic targeting of exportin-1 beyond nuclear export. Chen YF, Adams DJ
Trends Pharmacol Sci (Dec 2024)

Exportin-1 (XPO1), also known as chromosome region maintenance 1 (CRM1), directly binds to and mediates the nuclear export of hundreds of cargo proteins. Blocking nuclear export by the selective inhibitors of nuclear export (SINEs) is a validated therapeutic axis in cancer and an active area of research. However, a growing body of evidence implicates XPO1 in biological functions beyond nuclear export that include the regulation of mitosis and the epigenome. Additionally, new pharmacological classes of small molecules have emerged that degrade XPO1 or induce distinct cellular activity profiles. Here, we discuss the canonical model of nuclear export and XPO1's emergence as an anticancer target. We also spotlight the key evidence for underappreciated XPO1 functions and discuss the use of chemical probes to uncover new cellular roles for XPO1. With these growing trends, the field is poised to extend XPO1 therapeutic targeting to indications beyond oncology.]]> Wed, 31 Dec 1969 19:00:00 EST Prediction of Enhancer-Gene Interactions Using Chromatin-Conformation Capture and Epigenome Data Using STARE. Hecker D, Schulz MH
Methods Mol Biol (2025)

Disentangling the relationship of enhancers and genes is an ongoing challenge in epigenomics. We present STARE, our software to quantify the strength of enhancer-gene interactions based on enhancer activity and chromatin contact data. It implements the generalized Activity-by-Contact (gABC) score, which allows predicting putative target genes of candidate enhancers over any desired genomic distance. The only requirement for its application is a measurement of enhancer activity. In addition to regulatory interactions, STARE calculates transcription factor (TF) affinities on gene level. We illustrate its usage on a public single-cell data set of the human heart by predicting regulatory interactions on cell type level, by giving examples on how to integrate them with other data modalities, and by constructing TF affinity matrices.]]> Wed, 31 Dec 1969 19:00:00 EST Epigenetic Upregulation of Carotid Body Angiotensin Signaling Increases Blood Pressure. Zhu F, Wang Z, Davis K, McSwiggin H, Zyuzin J, Liu J, Yan W, Rehan VK, Jendzjowsky N
Hypertension (Dec 2024)

Epigenetic changes can be shaped by a wide array of environmental cues, maternal health, and behaviors. One of the most detrimental behaviors to the developing fetus is nicotine exposure. Perinatal nicotine exposure remains a significant risk factor for cardiovascular health and, in particular, hypertension. Increased basal carotid body (CB) activity and excitation are significant contributors to hypertension. This study investigated the epigenetic changes to CB activity induced by perinatal nicotine exposure resulting in CB-mediated hypertension.]]> Wed, 31 Dec 1969 19:00:00 EST Parent of origin genetic effects on milk production traits in a population of Iranian Holstein cows. Ghafouri-Kesbi F, Noorian M, Gholizadeh S, Mokhtari M
J Anim Breed Genet (Jan 2025)

The aim was to estimate the relative contribution of imprinting effects from both paternal and maternal sides to phenotypic variation in milk production traits including 305 days milk yield (MY), average daily milk production (ADM), fat percentage (F%), protein percentage (P%), 305 days fat yield (FY), 305 days protein yield (PY), ratio of fat percentage to protein percentage (F:P) and somatic cell score (SCS) in Iranian Holstein cows. To do this, each trait was analysed with a series of four animal models, which were identical for fixed and additive genetic effects but differed for combinations of paternal and maternal imprinting effects. The log-likelihood ratio test (LRT) and Akaike's information criteria (AIC) were used to select the best model for each trait. Correlations between traits due to additive and imprinting effects were estimated by bivariate analyses. For all traits studied, fitting the imprinting effect led to a better data fit. Also, it resulted in a noticeable decrease in additive genetic variance from 8% (SCS) to 28% (F:P). A significant maternal imprinting effect was detected on all traits studied. Estimates of maternal imprinting heritability ( ) were 0.07 ± 0.02, 0.04 ± 0.01, 0.06 ± 0.01, 0.05 ± 0.01, 0.5 ± 0.01, 0.09 ± 0.02, 0.07 ± 0.02 and 0.06 ± 0.01 for MY, ADM, F%, P%, FY, PY, F:P and SCS, respectively. For F:P, in addition to the maternal imprinting effect, a significant paternal imprinting component was also detected with a 7% contribution to phenotypic variance of F:P. Estimates of direct heritability ( ) were 0.29 ± 0.02, 0.17 ± 0.01, 0.22 ± 0.02, 0.11 ± 0.01, 0.18 ± 0.02, 0.22 ± 0.02, 0.15 ± 0.04 and 0.06 ± 0.01 for MY, ADM, F%, P%, FY, PY, F:P and SCS, respectively. Maternal imprinting correlations (r) were in a wide range between -0.75 ± 0.15 (P%-SCS) and 0.95 ± 0.11 (MY-ADM). Additive genetic correlations (r) ranged between -0.54 ± 0.05 (MY-P%) and 0.99 ± 0.01 (MY-ADM) and phenotypic correlations (r) ranged from -0.30 ± 0.01 (MY-F%) to 0.93 ± 0.01 (MY-ADM). The Spearman's correlation between additive breeding values including and excluding imprinting effects deviated from unity especially for top-ranked animals implying re-ranking of top animals following the inclusion of imprinting effects in the model. Since including imprinting effects in the model resulted in better data fit and re-ranking of top animals, including these effects in the genetic evaluation models for milk production traits was recommended.]]> Wed, 31 Dec 1969 19:00:00 EST A two-phase epigenome-wide four-way gene-smoking interaction study of overall survival for early-stage non-small cell lung cancer. Chen L, Wang X, Xie N, Zhang Z, Xu X, Xue M, Yang Y, Liu L, Su L, Bjaanæs M, Karlsson A, Planck M, Staaf J, Helland Ã…, Esteller M, Christiani DC, Chen F, Zhang R
Mol Oncol (Dec 2024)

High-order interactions associated with non-small cell lung cancer (NSCLC) survival may elucidate underlying molecular mechanisms and identify potential therapeutic targets. Our previous work has identified a three-way interaction among pack-year of smoking (the number of packs of cigarettes smoked per day multiplied by the number of years the person has smoked) and two DNA methylation probes (cg05293407 and cg00060500). However, whether a four-way interaction exists remains unclear. Therefore, we adopted a two-phase design to identify the four-way gene-smoking interactions by a hill-climbing strategy on the basis of the previously detected three-way interaction. One CpG probe, cg16658473, was identified with FDR-q ≤ 0.05 in the discovery phase and P ≤ 0.05 in the validation phase. Meanwhile, the four-way interaction improved the discrimination ability for the prognostic prediction model, as indicated by the area under the receiver operating characteristic curve (AUC) for both 3- and 5-year survival. In summary, we identified a four-way interaction associated with NSCLC survival among pack-year of smoking, cg05293407, cg00060500 and g16658473, providing novel insights into the complex mechanisms underlying NSCLC progression.]]> Wed, 31 Dec 1969 19:00:00 EST