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Epigenetic Impacts of non-coding mutations Deciphered Through Pre-Trained DNA Language Model at Single-Cell Resolution

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ADVANCED SCIENCE 2025年第11期12卷 e2413571页

作者： Liu, Zhe Gu, An Bao, Yihang Lin, Guan Ning Shanghai Jiao Tong Univ Shanghai Mental Hlth Ctr Sch Med Sch Biomed Engn Shanghai 200230 Peoples R China Shanghai Key Lab Psychot Disorders Shanghai 200230 Peoples R China Minist Educ Engn Res Ctr Digital Med Shanghai 200230 Peoples R China

DNA methylation plays a critical role in gene regulation, affecting cellular differentiation and disease progression, particularly in non-coding regions. However, predicting the epigenetic consequences of non-coding mutations at single-cell resolution remains a challenge. Existing tools have limited prediction capacity and struggle to capture dynamic, cell-type-specific regulatory changes that are crucial for understanding disease mechanisms. Here, Methven, a deep learning framework designed is presented to predict the effects of non-coding mutations on DNA methylation at single-cell resolution. Methven integrates DNA sequence with single-cell ATAC-seq data and models SNP-CpG interactions over 100 kbp genomic distances. By using a divide-and-conquer approach, Methven accurately predicts both short- and long-range regulatory interactions and leverages the pre-trained DNA language model for enhanced precision in classification and regression tasks. Methven outperforms existing methods and demonstrates robust generalizability to monocyte datasets. Importantly, it identifies CpG sites associated with rheumatoid arthritis, revealing key pathways involved in immune regulation and disease progression. Methven's ability to detect progressive epigenetic changes provides crucial insights into gene regulation in complex diseases. These findings demonstrate Methven's potential as a powerful tool for basic research and clinical applications, advancing this understanding of non-coding mutations and their role in disease, while offering new opportunities for personalized medicine.

关键词： deep learning DNA methylation non-coding mutations single-cell resolution SNP-CpG interactions

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Discovery of Cis-Regulatory Mechanisms via non-coding mutations in Acute Lymphoblastic Leukemia

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GENES CHROMOSOMES & CANCER 2025年第3期64卷 e70045页

作者： Aydin, Efe Woodward, Eleanor L. Dushime, Gladys Telliam Gunnarsson, Rebeqa Lilljebjorn, Henrik Moura-Castro, Larissa H. Fioretos, Thoas Johansson, Bertil Paulsson, Kajsa Yang, Minjun Lund Univ Dept Lab Med Div Clin Genet Lund Sweden Reg Skane Off Med Serv Dept Clin Genet Pathol & Mol Diagnost Lund Sweden Lund Univ Sci Life Lab Clin Genom Lund Lund Sweden

The non-coding genome, constituting 98% of human DNA, remains largely unexplored, yet holds potential for identifying new biomarkers and therapeutic targets in acute lymphoblastic leukemia (ALL). In this study, we conducted a systematic analysis of recurrent somatic non-coding single nucleotide variants (SNVs) in pediatric B-cell precursor (BCP) ALL. We leveraged whole genome sequencing (WGS) data from 345 pediatric BCP ALL cases, representing all major genetic subtypes and identified 346 mutational hotspots that harbored somatic SNVs in at least three cases. Through the integration of paired RNA sequencing along with published ChIP-seq and ATAC-seq data, we found 128 non-coding hotspots associated with differentially expressed genes nearby, which were enriched for cis-regulatory elements, demonstrating the effectiveness of multi-omics integration in distinguishing pathogenic mutations from passengers. We identified one mutational hotspot that was associated with increased expression of the leukemia-associated gene NRAS in three primary ALLs. Micro-C analysis in the leukemia cell line demonstrated interactions between the hotspot region and NRAS regulatory elements. Dual luciferase assays indicated that the mutations disrupted regulatory interactions and CRISPR-mediated deletion of the region significantly upregulated NRAS, confirming the hypothesized regulatory link. Altogether, we provide new insights into the functional roles of non-coding mutations in leukemia.

关键词： B-cell precursor acute lymphoblastic leukemia cis-regulatory elements leukemogenesis multi-omics non-coding mutations

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Reannotation of cancer mutations based on expressed RNA transcripts reveals functional non-coding mutations in melanoma

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American Journal of Human Genetics 2025年第6期112卷 1447-1467页

作者： Pepe, Daniele Janssens, Xander Timcheva, Kalina Marrón-Liñares, Grecia M. Verbelen, Benno Konstantakos, Vasileios De Groote, Dylan De Bie, Jolien Verhasselt, Amber Dewaele, Barbara Godderis, Arne Cools, Charlotte Franco-Tolsau, Mireia Royaert, Jonathan Verbeeck, Jelle Kampen, Kim R. Subramanian, Karthik Cabrerizo Granados, David Menschaert, Gerben De Keersmaecker, Kim Department of Oncology KU Leuven Leuven Belgium Leuven Cancer Institute (LKI) Leuven Belgium Department of Human Genetics KU Leuven Leuven Belgium VIB Center for AI & Computational Biology (VIB.AI) Leuven Belgium VIB-KU Leuven Center for Brain & Disease Research Leuven Belgium Center for Human Genetics University Hospitals Leuven Leuven Belgium OHMX.bio NV Evergem Belgium Department of Radiation Oncology (Maastro) GROW School for Oncology and Reproduction Maastricht University Medical Centre Maastricht Netherlands Department of Data Analysis and Mathematical Modelling Ghent University Ghent Belgium

The role of synonymous mutations in cancer pathogenesis is currently underexplored. We developed a method to detect significant clusters of synonymous and missense mutations in public cancer genomics data. In melanoma, we show that 22% (11/50) of these mutation clusters are misannotated as coding mutations because the reference transcripts used for their annotation are not expressed. Instead, these mutations are actually non-coding. This, for instance, applies to the mutation clusters targeting known cancer genes kinetochore localized astrin (SPAG5) binding protein (KNSTRN) and BCL2-like 12 (BCL2L12), each affecting 4%–5% of melanoma tumors. For the latter, we show that these mutations are functional non-coding mutations that target the shared promoter region of interferon regulatory factor 3 (IRF3) and BCL2L12. This results in downregulation of IRF3, BCL2L12, and tumor protein p53 (TP53) expression in a CRISPR-Cas9 primary melanocyte model and in melanoma tumors. In individuals with melanoma, these mutations were also associated with a worse response to immunotherapy. Finally, we propose a simple automated method to more accurately annotate cancer mutations based on expressed transcripts. This work shows the importance of integrating DNA- and RNA-sequencing data to properly annotate mutations and identifies a number of previously overlooked and wrongly annotated functional non-coding mutations in melanoma. © 2025 The Author(s)

关键词： bioinformatics CRISPR-Cas9 expressed transcript functional genomics gene regulation melanoma mutation annotation non-coding mutations synonymous mutations

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Prediction of non-coding Driver mutations Using Ensemble Learning

Prediction of Non-coding Driver Mutations Using Ensemble Lea...

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2023 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2023

作者： Basharat, Sana Huseynov, Ramal Kilinc, Huseyin Hilmi Otlu, Burcak Middle East Technical University Graduate School of Informatics Department of Data Informatics Ankara06800 Turkey Arçelik A.Ş. Refrigerator Plant Research and Development Center Eskişehir26110 Turkey Middle East Technical University Graduate School of Informatics Department of Health Informatics Ankara06800 Turkey

ISBN: (纸本)9798350337488

Driver coding mutations are extensively studied and frequently detected by their deleterious amino acid changes that affect protein function. However, non-coding mutations need further analysis and experimental validation to determine them as driver non-coding mutations. Here, we employ the XGBoost (eXtreme Gradient Boosting) algorithm to predict driver non-coding mutations based on novel long-range interaction features and engineered transcription factor binding site features augmented with features from existing annotation and effect prediction tools. Regarding novel long-range interaction features, we capture the frequency and spread of interacting regions overlapping with the non-coding mutation of interest. For this purpose, we use self-balancing trees to find overlaps within chromatin loop files and store the interacting regions as separate tree structures. For engineered transcription factor (TF) binding features, we train TF models utilizing the stochastic gradient descent (SGD) algorithm to predict the loss and gain of functions at transcription factor binding sites by giving more weight to the non-coding mutations affecting transcription factor binding affinities. We also include features from existing annotation and effect prediction tools;some rely on deep learning methods relating to splicing effect, number of associated protein products, variant consequences, biotypes, and others. For the known driver and non-driver non-coding mutations, the resulting aggregated dataset is trained with our gradient boosting model to predict driver versus passenger non-coding mutations. We then use non-coding driver mutations found in other state-of-the-art studies, similarly annotate them, and pass them through our model to make a comparison. Furthermore, we elaborate on the results by using explainable AI methodologies. Our results show an above-average performance on the unseen test data and suggest that using our annotations and training the resulting data using gra

关键词： Boosting Driver mutations Ensemble Learning Explainable AI Long-range Interactions non-coding mutations

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Comparative analysis of non-coding and coding DNA mutations in flat urothelial lesions: biological implications and insights

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VIRCHOWS ARCHIV 2025年第4期486卷 729-737页

作者： Musangile, Fidele Y. Matsuzaki, Ibu Iwamoto, Ryuta Sagan, Kanako Nishikawa, Mizuki Mikasa, Yurina Takahashi, Yuichi Higashine, Ryoma Kojima, Fumiyoshi Hara, Isao Murata, Shin-ichi Wakayama Med Univ Dept Human Pathol 811-1 Kimiidera Wakayama 6418509 Japan Wakayama Med Univ Dept Urol Wakayama Japan

Recent research in urothelial carcinoma (UC) has focused on coding mutations, leaving the significance of non-coding mutations unexplored. This study aims to evaluate non-coding DNA mutation frequencies compared to coding regions in normal urothelium and flat lesions, exploring their implications for tumor biology. Using targeted next-generation sequencing with UC-related gene panel, we analyzed non-coding and coding DNA mutation frequencies across 119 samples of flat urothelium encompassing various lesion types. Mutation patterns were examined based on the presence of associated flat or papillary tumors, and we investigated the correlation between mutation rates in target genes and genetic mutations within genomic regions. Intronic mutations (IMs) displayed variability across lesions, with normal urothelium (NU) exhibiting the highest frequency (43%) and urothelial carcinoma in situ (CIS) the lowest (9%). We observed similar sets of frequently mutated genes in both intronic and exonic regions, distinct from promoter region mutations. Although IMs paralleled exonic mutations in NU, reactive atypia, and atypia of unknown significance (AUS), they were less prevalent in dysplasia (DYS) and CIS. In contrast to CIS-associated AUS and DYS lesions, AUS-DYS lesions associated with papillary tumors exclusively exhibited recurrent intronic mutations involving FGFR3 and ERCC2, aligning with mutation patterns seen in exonic regions. ERCC2 intronic mutations correlated with the mutation rates of the gene panel. Our findings suggest that intronic mutations significantly contribute to tumor heterogeneity in urothelial lesions and may potentially be linked to genomic instability, warranting further investigation.

关键词： Flat urothelial lesion Intronic mutation Next-generation sequencing non-coding mutations Urothelial carcinoma

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non-synonymous, synonymous, and non-coding nucleotide variants contribute to recurrently altered biological processes during retinoblastoma progression

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GENES CHROMOSOMES & CANCER 2023年第5期62卷 275-289页

作者： Stachelek, Kevin Harutyunyan, Narine Lee, Susan Beck, Assaf Kim, Jonathan Xu, Liya Berry, Jesse L. Nagiel, Aaron Reynolds, C. Patrick Murphree, A. Linn Lee, Thomas C. Aparicio, Jennifer G. Cobrinik, David Childrens Hosp Los Angeles Vis Ctr Los Angeles CA USA Childrens Hosp Los Angeles Saban Res Inst Los Angeles CA USA Univ Southern Calif Keck Sch Med Canc Biol & Genom Program Los Angeles CA USA Univ Southern Calif Keck Sch Med Dept Ophthalmol Los Angeles CA USA Univ Southern Calif Roski Eye Inst Keck Sch Med Los Angeles CA USA Univ Southern Calif Norris Comprehens Canc Ctr Keck Sch Med Los Angeles CA USA Texas Tech Univ Sch Med Dept Pediat Hlth Sci Ctr Lubbock TX USA Texas Tech Univ Canc Ctr Sch Med Hlth Sci Ctr Lubbock TX USA Univ Southern Calif Keck Sch Med Dept Biochem & Mol Med Los Angeles CA USA Childrens Hosp Los Angeles 4650 Sunset BlvdMS 163 Los Angeles CA 90027 USA

Retinoblastomas form in response to biallelic RB1 mutations or MYCN amplification and progress to more aggressive and therapy-resistant phenotypes through accumulation of secondary genomic changes. Progression-related changes include recurrent somatic copy number alterations and typically non-recurrent nucleotide variants, including synonymous and non-coding variants, whose significance has been unclear. To determine if nucleotide variants recurrently affect specific biological processes, we identified altered genes and over-represented variant gene ontologies in 168 exome or whole-genome-sequenced retinoblastomas and 12 tumor-matched cell lines. In addition to RB1 mutations, MYCN amplification, and established retinoblastoma somatic copy number alterations, the analyses revealed enrichment of variant genes related to diverse biological processes including histone monoubiquitination, mRNA processing (P) body assembly, and mitotic sister chromatid segregation and cytokinesis. Importantly, non-coding and synonymous variants increased the enrichment significance of each over-represented biological process term. To assess the effects of such mutations, we examined the consequences of a 3' UTR variant of PCGF3 (a BCOR-binding component of Polycomb repressive complex I), dual 3' UTR variants of CDC14B (a regulator of sister chromatid segregation), and a synonymous variant of DYNC1H1 (a regulator of P-body assembly). One PCGF3 and one of two CDC14B 3' UTR variants impaired gene expression whereas a base-edited DYNC1H1 synonymous variant altered protease sensitivity and stability. Retinoblastoma cell lines retained only similar to 50% of variants detected in tumors and enriched for new variants affecting p53 signaling. These findings reveal potentially important differences in retinoblastoma cell lines and tumors and implicate synonymous and non-coding variants, along with non-synonymous variants, in retinoblastoma oncogenesis.

关键词： cancer progression non-coding mutations retinoblastoma synonymous mutations

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Position effects at the FGF8 locus are associated with femoral hypoplasia

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AMERICAN JOURNAL OF HUMAN GENETICS 2021年第9期108卷 1725-1734页

作者： Socha, Magdalena Sowinska-Seidler, Anna Melo, Uira Souto Kragesteen, Bjort K. Franke, Martin Heinrich, Verena Schopflin, Robert Nagel, Inga Gruchy, Nicolas Mundlos, Stefan Sreenivasan, Varun K. A. Lopez, Cristina Vingron, Martin Bukowska-Olech, Ewelina Spielmann, Malte Jamsheer, Aleksander Poznan Univ Med Sci Dept Med Genet PL-60806 Poznan Poland Max Planck Inst Mol Genet RG Dev & Dis D-14195 Berlin Germany Charite Univ Med Berlin Inst Med & Human Genet D-10117 Berlin Germany Weizmann Inst Sci Dept Immunol IL-76100 Rehovot Israel Univ Pablo de Olavide Ctr Andaluz Biol Desarrollo CSIC Seville 41013 Spain Max Planck Inst Mol Genet Dept Computat Mol Biol D-14195 Berlin Germany Univ Klinikum Schleswig Holstein Inst Human Genet Campus Kiel D-24105 Kiel Germany Univ Kiel D-24105 Kiel Germany Normandie Univ Dept Genet EA7450 BioTARGen UNICAENCHU Caen Normandie F-14000 Caen France Charite Univ Med Berlin Berlin Brandenburg Ctr Regenerat Therapies D-13353 Berlin Germany Univ Klinikum Schleswig Holstein Inst Human Genet Campus Lubeck D-23562 Lubeck Germany Univ Lubeck D-23562 Lubeck Germany Inst Invest Biomed August Pi & Sunyer Ciber Canc Barcelona Spain Ctr Invest Biomed Red Canc Madrid Spain Max Planck Inst Mol Genet Human Mol Genom Grp D-14195 Berlin Germany Ctr Med Genet GENESIS PL-60529 Poznan Poland

Copy-number variations (CNVs) are a common cause of congenital limb malformations and are interpreted primarily on the basis of their effect on gene dosage. However, recent studies show that CNVs also influence the 3D genome chromatin organization. The functional interpretation of whether a phenotype is the result of gene dosage or a regulatory position effect remains challenging. Here, we report on two unrelated families with individuals affected by bilateral hypoplasia of the femoral bones, both harboring de novo duplications on chromosome 10q24.32. The similar to 0.5 Mb duplications include FGF8, a key regulator of limb development and several limb enhancer elements. To functionally characterize these variants, we analyzed the local chromatin architecture in the affected individuals' cells and re-engineered the duplications in mice by using CRISPR-Cas9 genome editing. We found that the duplications were associated with ectopic chromatin contacts and increased FGF8 expression. Transgenic mice carrying the heterozygous tandem duplication including Fgf8 exhibited proximal shortening of the limbs, resembling the human phenotype. To evaluate whether the phenotype was a result of gene dosage, we generated another transgenic mice line, carrying the duplication on one allele and a concurrent Fgf8 deletion on the other allele, as a control. Surprisingly, the same malformations were observed. Capture Hi-C experiments revealed ectopic interaction with the duplicated region and Fgf8, indicating a position effect. In summary, we show that duplications at the FGF8 locus are associated with femoral hypoplasia and that the phenotype is most likely the result of position effects altering FGF8 expression rather than gene dosage effects.

关键词： TADs position effects FGF8 non-coding mutations femoral hypoplasia enhancer

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Etiology of super-enhancer reprogramming and activation in cancer

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EPIGENETICS & CHROMATIN 2023年第1期16卷 29-29页

作者： Zhou, Royce W. Parsons, Ramon E. Icahn Sch Med Mt Sinai Tich Canc Inst New York NY 10029 USA Icahn Sch Med Mt Sinai Dept Oncol Sci New York NY 10029 USA Univ Calif San Francisco Mol Med Program San Francisco CA USA

Super-enhancers are large, densely concentrated swaths of enhancers that regulate genes critical for cell identity. Tumorigenesis is accompanied by changes in the super-enhancer landscape. These aberrant super-enhancers commonly form to activate proto-oncogenes, or other genes upon which cancer cells depend, that initiate tumorigenesis, promote tumor proliferation, and increase the fitness of cancer cells to survive in the tumor microenvironment. These include well-recognized master regulators of proliferation in the setting of cancer, such as the transcription factor MYC which is under the control of numerous super-enhancers gained in cancer compared to normal tissues. This Review will cover the expanding cell-intrinsic and cell-extrinsic etiology of these super-enhancer changes in cancer, including somatic mutations, copy number variation, fusion events, extrachromosomal DNA, and 3D chromatin architecture, as well as those activated by inflammation, extra-cellular signaling, and the tumor microenvironment.

关键词： Enhancers Super-enhancers Cancer Extrachromosomal DNA Topologically associated domain non-coding mutations Phase separation Inflammation Therapeutic resistance Insulators Tumor microenvironment

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Deep whole genome sequencing identifies recurrent genomic alterations in commonly used breast cancer cell lines and patient-derived xenograft models

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BREAST CANCER RESEARCH 2022年第1期24卷 63-63页

作者： Deng, Niantao Minoche, Andre Harvey, Kate Li, Meng Winkler, Juliane Goga, Andrei Swarbrick, Alex Garvan Inst Med Res Canc Ecosyst Program Sydney NSW Australia UNSW Sydney Sch Clin Med Fac Med & Hlth Sydney NSW Australia Garvan Inst Med Res Kinghorn Ctr Clin Genom Sydney NSW Australia Univ Calif San Francisco Dept Cell & Tissue Biol San Francisco CA 94143 USA Univ Calif San Francisco Dept Med San Francisco CA 94143 USA

Breast cancer cell lines (BCCLs) and patient-derived xenografts (PDXs) are the most frequently used models in breast cancer research. Despite their widespread usage, genome sequencing of these models is incomplete, with previous studies only focusing on targeted gene panels, whole exome or shallow whole genome sequencing. Deep whole genome sequencing is the most sensitive and accurate method to detect single nucleotide variants and indels, gene copy number and structural events such as gene fusions. Results Here we describe deep whole genome sequencing (WGS) of commonly used BCCL and PDX models using the Illumina X10 platform with an average similar to 60 x coverage. We identify novel genomic alterations, including point mutations and genomic rearrangements at base-pair resolution, compared to previously available sequencing data. Through integrative analysis with publicly available functional screening data, we annotate new genomic features likely to be of biological significance. CSMD1, previously identified as a tumor suppressor gene in various cancer types, including head and neck, lung and breast cancers, has been identified with deletion in 50% of our PDX models, suggesting an important role in aggressive breast cancers. Conclusions Our WGS data provides a comprehensive genome sequencing resource of these models.

关键词： Breast cancer cell lines Patient-derived xenografts Whole genome sequencing Structural variants non-coding mutations

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non-coding regulatory elements: Potential roles in disease and the case of epilepsy

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NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY 2022年第3期48卷 e12775-e12775页

作者： Pagni, Susanna Mills, James D. Frankish, Adam Mudge, Jonathan M. Sisodiya, Sanjay M. UCL Queen Sq Inst Neurol Dept Clin & Expt Epilepsy Box 29Queen Sq London WC1N 3BG England Chalfont Ctr Epilepsy Gerrards Cross England Univ Amsterdam Dept Neuro Pathol Amsterdam Neurosci Amsterdam UMC Amsterdam Netherlands European Bioinformat Inst European Mol Biol Lab Cambridge England

non-coding DNA (ncDNA) refers to the portion of the genome that does not code for proteins and accounts for the greatest physical proportion of the human genome. ncDNA includes sequences that are transcribed into RNA molecules, such as ribosomal RNAs (rRNAs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and un-transcribed sequences that have regulatory functions, including gene promoters and enhancers. Variation in non-coding regions of the genome have an established role in human disease, with growing evidence from many areas, including several cancers, Parkinson's disease and autism. Here, we review the features and functions of the regulatory elements that are present in the non-coding genome and the role that these regions have in human disease. We then review the existing research in epilepsy and emphasise the potential value of further exploring non-coding regulatory elements in epilepsy. In addition, we outline the most widely used techniques for recognising regulatory elements throughout the genome, current methodologies for investigating variation and the main challenges associated with research in the field of non-coding DNA.

关键词： epilepsy gene regulation non-coding DNA non-coding mutations regulatory sequences

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