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Protection of the genome and the central exome by peripheral non-coding dna against dna damage in health, ageing and age-related diseases

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BIOLOGICAL REVIEWS 2025年第2期100卷 508-529页

作者： Qiu, Guo-Hua Fu, Mingjun Zheng, Xintian Huang, Cuiqin Longyan Univ Coll Life Sci Longyan 364012 Peoples R China Fujian Prov Univ Engn Res Ctr Prevent & Control Anim Origin Zoonosi Fujian Prov Key Lab Prevent Vet Med & Biotechnol Key Lab Prevent & Control Anim Infect Dis & Biotec Longyan Peoples R China

dna in eukaryotic genomes is under constant assault from both exogenous and endogenous sources, leading to dna damage, which is considered a major molecular driver of ageing. Fortunately, the genome and the central exome are safeguarded against these attacks by abundant peripheral non-coding dna. non-coding dna codes for small non-coding RNAs that inactivate foreign nucleic acids in the cytoplasm and physically blocks these attacks in the nucleus. Damage to non-coding dna produced during such blockage is removed in the form of extrachromosomal circular dna (eccdna) through nucleic pore complexes. Consequently, non-coding dna serves as a line of defence for the exome against dna damage. The total amount of non-coding dna/heterochromatin declines with age, resulting in a decrease in both physical blockage and eccdna exclusion, and thus an increase in the accumulation of dna damage in the nucleus during ageing and in age-related diseases. Here, we summarize recent evidence supporting a protective role of non-coding dna in healthy and pathological states and argue that dna damage is the proximate cause of ageing and age-related genetic diseases. Strategies aimed at strengthening the protective role of non-coding dna/heterochromatin could potentially offer better systematic protection for the dynamic genome and the exome against diverse assaults, reduce the burden of dna damage to the exome, and thus slow ageing, counteract age-related genetic diseases and promote a healthier life for individuals.

关键词： non-coding dna genome defence exome dna damage eccdna nucleic pore complex ageing age-related diseases

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The protective function of non-coding dna in dna damage accumulation with age and its roles in age-related diseases

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BIOGERONTOLOGY 2019年第6期20卷 741-761页

作者： Qiu, Guo-Hua Zheng, Xintian Fu, Mingjun Huang, Cuiqin Yang, Xiaoyan Longyan Univ Fujian Prov Key Lab Prevent & Control Anim Infect Longyan 364012 Peoples R China Longyan Univ Fujian Prov Univ Key Lab Prevent Vet Med & Biotechnol Longyan 364012 Peoples R China Longyan Univ Coll Life Sci Longyan 364012 Peoples R China

Aging is a progressive decline of physiological function in tissue and organ accompanying both accumulation of dna damage and reduction of non-coding dna. Peripheral non-coding dna/heterochromatin has been proposed to protect the genome and centrally-located protein-coding sequences in soma and male germ cells against radiation and the invasion of exogenous nucleic acids. Therefore, this review summarizes the reduction of non-coding dna/heterochromatin (including telomeric dna and rdna) and dna damage accumulation during normal physiological aging and in various aging-related diseases. Based on analysis of data, it is found that dna damage accumulation is roughly negatively correlated with the reduction of non-coding dna and therefore speculated that dna damage accumulation is likely due to the reduction of non-coding dna protection in genome defense during aging. Therefore, it is proposed here that means to increase the total amount of non-coding dna and/or heterochromatin prior to the onset of these diseases could potentially better protect the genome and protein-coding dna, reduce the incidence of aging-related diseases, and thus lead to better health during aging.

关键词： non-coding dna dna damage accumulation Aging-related diseases Peripheral heterochromatin Genome protection

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Functional interrogation of non-coding dna through CRISPR genome editing

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METHODS 2017年 121卷 118-129页

作者： Canver, Matthew C. Bauer, Daniel E. Orkin, Stuart H. Harvard Med Sch Boston MA 02115 USA Boston Childrens Hosp Div Hematol Oncol Boston MA 02115 USA Dana Farber Canc Inst Dept Pediat Oncol Boston MA 02115 USA Howard Hughes Med Inst Boston MA 02115 USA

Methodologies to interrogate non-coding regions have lagged behind coding regions despite comprising the vast majority of the genome. However, the rapid evolution of clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing has provided a multitude of novel techniques for laboratory investigation including significant contributions to the toolbox for studying non-coding dna. CRISPR-mediated loss-of-function strategies rely on direct disruption of the underlying sequence or repression of transcription without modifying the targeted dna sequence. CRISPR-mediated gain of -function approaches similarly benefit from methods to alter the targeted sequence through integration of customized sequence into the genome as well as methods to activate transcription. Here we review CRISPR-based loss-and gain-of-function techniques for the interrogation of non-coding dna. (C) 2017 Elsevier Inc. All rights reserved.

关键词： non-coding dna CRISPRS (Genetics) GENOME editing EVOLUTION (Biology) PALINDROMIC dna MUTATION (Biology)

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An Abundant Class of non-coding dna Can Prevent Stochastic Gene Silencing in the C. elegans Germline

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CELL 2016年第2期166卷 343-357页

作者： Frokjaer-Jensen, Christian Jain, Nimit Hansen, Loren Davis, M. Wayne Li, Yongbin Zhao, Di Rebora, Karine Millet, Jonathan R. M. Liu, Xiao Kim, Stuart K. Dupuy, Denis Jorgensen, Erik M. Fire, Andrew Z. Univ Utah Howard Hughes Med Inst Dept Biol Salt Lake City UT 84112 USA Stanford Univ Dept Pathol Stanford CA 94305 USA Univ Copenhagen Dept Biomed Sci DK-2200 Copenhagen N Denmark Univ Copenhagen Danish Natl Res Fdn Ctr Cardiac Arrhythmia DK-2200 Copenhagen N Denmark Stanford Univ Sch Med Dept Bioengn Stanford CA 94305 USA Stanford Univ Med Ctr Dept Dev Biol Stanford CA 94305 USA Univ Bordeaux IECB Lab ARNA INSERMU869 F-33600 Pessac France Stanford Univ Dept Genet Stanford CA 94305 USA Tsinghua Univ Sch Life Sci Beijing 100084 Peoples R China

Cells benefit from silencing foreign genetic elements but must simultaneously avoid inactivating endogenous genes. Although chromatin modifications and RNAs contribute to maintenance of silenced states, the establishment of silenced regions will inevitably reflect underlying dna sequence and/or structure. Here, we demonstrate that a pervasive non-coding dna feature in Caenorhabditis elegans, characterized by 10-base pair periodic A(n)/T-n-clusters ( PATCs), can license transgenes for germline expression within repressive chromatin domains. Transgenes containing natural or synthetic PATCs are resistant to position effect variegation and stochastic silencing in the germline. Among endogenous genes, intron length and PATC-character undergo dramatic changes as orthologs move from active to repressive chromatin over evolutionary time, indicating a dynamic character to the A(n)/T-n periodicity. We propose that PATCs form the basis of a cellular immune system, identifying certain endogenous genes in heterochromatic contexts as privileged while foreign dna can be suppressed with no requirement for a cellular memory of prior exposure.

关键词： Caenorhabditis elegans -- Genetics non-coding dna Gene silencing Nucleotide sequence Germ cells Transgenes

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Genome defense against exogenous nucleic acids in eukaryotes by non-coding dna occurs through CRISPR-like mechanisms in the cytosol and the bodyguard protection in the nucleus

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MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2016年第0期767卷 31-41页

作者： Qiu, Guo-Hua Changzhou Univ Changzhou Jiangsu Peoples R China

In this review, the protective function of the abundant non-coding dna in the eukaryotic genome is discussed from the perspective of genome defense against exogenous nucleic acids. Peripheral non coding dna has been proposed to act as a bodyguard that protects the genome and the central protein coding sequences from ionizing radiation-induced dna damage. In the proposed mechanism of protection, the radicals generated by water radiolysis in the cytosol and IR energy are absorbed, blocked and/or reduced by peripheral heterochromatin;then, the dna damage sites in the heterochromatin are removed and expelled from the nucleus to the cytoplasm through nuclear pore complexes, most likely through the formation of extrachromosomal circular dna. To strengthen this hypothesis, this review summarizes the experimental evidence supporting the protective function of non-coding dna against exogenous nucleic acids. Based on these data, I hypothesize herein about the presence of an additional line of defense formed by small RNAs in the cytosol in addition to their bodyguard protection mechanism in the nucleus. Therefore, exogenous nucleic acids may be initially inactivated in the cytosol by small RNAs generated from non-coding dna via mechanisms similar to the prokaryotic CRISPR-Cas system. Exogenous nucleic acids may enter the nucleus, where some are absorbed and/or blocked by heterochromatin and others integrate into chromosomes. The integrated fragments and the sites of dna damage are removed by repetitive non-coding dna elements in the heterochromatin and excluded from the nucleus. Therefore, the normal eukaryotic genome and the central protein-coding sequences are triply protected by non-coding dna against invasion by exogenous nucleic acids. This review provides evidence supporting the protective role of non-coding dna in genome defense. (C) 2016 Elsevier B.V. All rights reserved.

关键词： non-coding dna Genome defense CRISPR-like Bodyguard protection Viruses

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Protection of the genome and central protein-coding sequences by non-coding dna against dna damage from radiation

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MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2015年 764卷 108-117页

作者： Qiu, Guo-Hua Changzhou Univ Inst Biomed Engn & Hlth Sci Changzhou Jiangsu Peoples R China

non-coding dna comprises a very large proportion of the total genomic content in higher organisms, but its function remains largely unclear. non-coding dna sequences constitute the majority of peripheral heterochromatin, which has been hypothesized to be the genome's 'bodyguard' against dna damage from chemicals and radiation for almost four decades. The bodyguard protective function of peripheral heterochromatin in genome defense has been strengthened by the results from numerous recent studies, which are summarized in this review. These data have suggested that cells and/or organisms with a higher level of heterochromatin and more non-coding dna sequences, including longer telomeric dna and rdnas, exhibit a lower frequency of dna damage, higher radioresistance and longer lifespan after IR exposure. In addition, the majority of heterochromatin is peripherally located in the three-dimensional structure of genome organization. Therefore, the peripheral heterochromatin with non-coding dna could play a protective role in genome defense against dna damage from ionizing radiation by both absorbing the radicals from water radiolysis in the cytosol and reducing the energy of IR. However, the bodyguard protection by heterochromatin has been challenged by the observation that dna damage is less frequently detected in peripheral heterochromatin than in euchromatin, which is inconsistent with the expectation and simulation results. Previous studies have also shown that the dna damage in peripheral heterochromatin is rarely repaired and moves more quickly, broadly and outwardly to approach the nuclear pore complex (NPC). Additionally, it has been shown that extrachromosomal circular dnas (eccdnas) are formed in the nucleus, highly detectable in the cytoplasm (particularly under stress conditions) and shuttle between the nucleus and the cytoplasm. Based on these studies, this review speculates that the sites of dna damage in peripheral heterochromatin could occur more frequently

关键词： non-coding dna Peripheral heterochromatin Genome protection dna damage Radiation

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non-canonical antigens are the largest fraction of peptides presented by MHC class I in mismatch repair deficient murine colorectal cancer

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GENOME MEDICINE 2024年第1期16卷 1-17页

作者： Rospo, Giuseppe Chila, Rosaria Matafora, Vittoria Basso, Veronica Lamba, Simona Bartolini, Alice Bachi, Angela Di Nicolantonio, Federica Mondino, Anna Germano, Giovanni Bardelli, Alberto Univ Torino Mol Biotechnol Ctr Dept Oncol Turin Italy IFOM ETS AIRC Inst Mol Oncol I-20139 Milan Italy IRCCS San Raffaele Sci Inst Div Immunol Transplantat & Infect Dis Lymphocyte Activat Unit Via Olgettina 58 I-20132 Milan Italy FPO IRCCS Candiolo Canc Inst I-10060 Candiolo TO Italy Boehringer Ingelheim RCV GmbH & Co KG Vienna Austria

BackgroundImmunotherapy based on checkpoint inhibitors is highly effective in mismatch repair deficient (MMRd) colorectal cancer (CRC). These tumors carry a high number of mutations, which are predicted to translate into a wide array of neoepitopes;however, a systematic classification of the neoantigen repertoire in MMRd CRC is lacking. Mass spectrometry peptidomics has demonstrated the existence of MHC class I associated peptides (MAPs) originating from non-coding dna regions. Based on these premises we investigated dna genomic regions responsible for generating MMRd-induced *** exploited mouse CRC models in which the MMR gene Mlh1 was genetically inactivated. Isogenic cell lines CT26 Mlh1+/+ and Mlh1-/- were inoculated in immunocompromised and immunocompetent mice. Whole genome and RNA sequencing data were generated from samples obtained before and after injection in murine hosts. First, peptide databases were built from transcriptomes of isogenic cell lines. We then compiled a database of peptides lost after tumor cells injection in immunocompetent mice, likely due to immune editing. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and matched next-generation sequencing databases were employed to identify the dna regions from which the immune-targeted MAPs originated. Finally, we adopted in vitro T cell assays to verify whether MAP-specific T cells were part of the in vivo immune response against Mlh1-/- *** genome sequencing analyses revealed an unbalanced distribution of immune edited alterations across the genome in Mlh1-/- cells grown in immunocompetent mice. Specifically, untranslated (UTR) and coding regions exhibited the largest fraction of mutations leading to highly immunogenic peptides. Moreover, the integrated computational and LC-MS/MS analyses revealed that MAPs originate mainly from atypical translational events in both Mlh1+/+ and Mlh1-/- tumor cells. In addition, mutated MAPs-derived from UTRs and out-of-fram

关键词： Colorectal cancer Mismatch repair Neoantigens non-coding dna non-canonical antigens Immune surveillance Next-generation sequencing HLA-peptidomics MAPs

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Design of an Efficient Model for Detecting Diseases using Genomics with Graph Relationship Networks 4

Design of an Efficient Model for Detecting Diseases using Ge...

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4th International Conference on Artificial Intelligence and Signal Processing

作者： Alparthi, Kumuda Panigrahy, Saroj Kumar VIT AP Univ Sch Comp Sci & Engn Amaravati Andhra Pradesh 522241 India

ISBN: (纸本)9798350350661;9798350350654

This paper introduces novel approaches utilizing Convolutional Neural Networks (CNNs), Recurrent Neural Networks (RNNs), Deep Autoencoders, and Graph Neural Networks (GNNs) in genomics. As the existing methods, while valuable, have limitations that hinder their effectiveness and often struggle with precision, accuracy, and speed in genome classification, leading to suboptimal results. Moreover, their inability to efficiently analyze multiple omics data and non-coding dna limits our understanding of complex disease mechanisms. In contrast, our proposed models harness the power of CNNs for identifying disease-related genetic markers, achieving automatic feature detection, reducing bias, and enhancing accuracy. Additionally, the utilization of RNNs, specifically Long Short-Term Memory (LSTM) networks, enables the precise annotation of genomic variants by understanding long-term dependencies in genetic sequences. Deep Autoencoders facilitate comprehensive disease analysis and Graph Neural Networks (GNNs) delve into non-coding dna, revealing intricate regulatory mechanisms and functions previously hidden. Our models exhibit a remarkable 9.5% improvement in genome classification precision, 8.5% higher accuracy, 6.5% enhanced recall, 8.3% increased speed, and a 10.5% superior Area Under the Curve (AUC) when compared to existing methods. This paper represents a significant step forward in genomics research, paving the way for more precise diagnostics and treatments for genetic diseases.

关键词： Genomics Deep Learning Convolutional Neural Networks Recurrent Neural Networks Multi-Omics Data non-coding dna Disease Analysis

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Eight Novel Microsatellite Loci in a Declining Grassland Songbird, the Bobolink (Dolichonyx oryzivorus)

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ECOLOGY AND EVOLUTION 2025年第5期15卷 e71400页

作者： McGee, Kathryn Perlut, Noah G. Travis, Steven E. Univ New England Sch Biol Sci Biddeford ME 04005 USA Univ New England Sch Marine & Environm Programs Biddeford ME USA

Microsatellite loci in non-coding regions of nuclear dna provide an important tool for genetic diversity research, particularly when comparing relatedness between individuals. While microsatellites have been developed for several species within the Blackbird family (Icteridae), no species-specific microsatellite primers for genetic analysis of Bobolinks (Dolichonyx oryzivorus) exist. Like many grassland songbirds, Bobolink populations are in decline, and accessible genetic analysis tools are therefore critical for understanding population dynamics. This paper introduces ten new, polymorphic microsatellite loci, at least eight of which should provide a reliable tool for the future study and monitoring of Bobolink genetics. These hypervariable and thus highly informative loci were amplified in 152 adult individuals from a well-studied population in Shelburne, Vermont, USA.

关键词： Hardy-Weinberg equilibrium microsatellite migratory songbird non-coding dna

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Long-read dna sequencing reveals the organization of the mitochondrial genome in the early-branching dinoflagellate Oxyrrhis marina.

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PROTIST 2024年第6期175卷 126071页

作者： Haro, Ronie Walunjkar, Nikita Jorapur, Soham Slamovits, Claudio H. Dalhousie Univ Inst Comparat Genom 5850 Coll St Halifax NS Canada Dalhousie Univ Dept Biochem & Mol Biol 5850 Coll StRm 8B1 Halifax NS B3H 4R2 Canada Indian Inst Sci Educ & Res Dept Biol Sci 77QG F7Q IISER Bhopal Rd Bhopal India

The mitochondrial genomes of dinoflagellate protists are remarkable for their highly fragmented and heterogeneous organization. Early attempts to determine their structure without 'next-generation' dna sequencing failed to recover a defined genome. Still, it coincided in showing that the proteins coding genes, three in total, and parts of the ribosomal RNA genes were spread across a diffuse assortment of small linear fragments. In contrast, a recent study employed Illumina sequencing to assemble a 326 kbp long single-molecule, circular mitochondrial genome in the symbiotic dinoflagellate Breviolum minutum. Here, we used a combination of short- and long-read massively-parallel dna sequencing to analyze further the mitochondrial dna of the early- branching dinoflagellate Oxyrrhis marina. We found that the mitochondrial genome of O. marina consists of 3 linear chromosomes sized 15.9, 33.8 and 40.6 kbp for a total of 90.3 kbp. It contains the cox 1, cox3 and cob genes, the same three proteins encoded in the mitochondrion of all myzozoans (Apicomplexa and Dinophyceae), some fragments of ribosomal RNA genes as well as many non-functional gene fragments and extensive noncoding dna. Our analysis unveiled segments syntenic patterns and rearrangements encompassing coding and non- coding regions, suggesting that recombination is a pervasive process driving the evolution of these genomes.

关键词： Alveolate Dinophyceae Mitochondria non-coding dna Recombination Ribosomal RNA

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