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noncoding Genomics in Gastric Cancer and the Gastric Precancerous Cascade: Pathogenesis and Biomarkers

DISEASE MARKERS 2015年第1期2015卷 1-14页

作者： Sandoval-Borquez, Alejandra Saavedra, Kathleen Carrasco-Avino, Gonzalo Garcia-Bloj, Benjamin Fry, Jacqueline Wichmann, Ignacio Corvalan, Alejandro H. Pontificia Univ Catolica Chile Adv Ctr Chron Dis ACCDiS Santiago 8330034 Chile Univ La Frontera Sci & Technol Bioresource Nucleus BIOREN Temuco 4811230 Chile Univ La Frontera Grad Program Appl Cell & Mol Biol Temuco 4811230 Chile Pontificia Univ Catolica Chile UC Ctr Invest Oncol CITO Santiago 8330034 Chile Univ Chile Dept Pathol Santiago 8380453 Chile Icahn Sch Med Mt Sinai Dept Pathol New York NY 10029 USA Pontificia Univ Catolica Chile Fac Med Dept Hematol Oncol Santiago 8330034 Chile

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death, whose patterns vary among geographical regions and ethnicities. It is a multifactorial disease, and its development depends on infection by Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), host genetic factors, and environmental factors. The heterogeneity of the disease has begun to be unraveled by a comprehensive mutational evaluation of primary tumors. The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics. noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through dna methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics. These processes and molecules ultimately control gene expression. Potential biomarkers are appearing from analyses of noncoding genomics. This review focuses on noncoding genomics and potential biomarkers in the context of gastric cancer and the gastric precancerous cascade.

关键词： non-coding dna STOMACH cancer CARCINOGENESIS BIOCHEMICAL markers dna methylation

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Cellular Senescence in Yeast Is Regulated by rdna noncoding Transcription

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CURRENT BIOLOGY 2013年第18期23卷 1794-1798页

作者： Saka, Kimiko Ide, Satoru Ganley, Austen R. D. Kobayashi, Takehiko Grad Univ Adv Studies Natl Inst Genet Cytogenet Div Mishima Shizuoka 4118540 Japan Grad Univ Adv Studies Dept Genet Mishima Shizuoka 4118540 Japan Massey Univ Inst Nat & Math Sci Auckland 0632 New Zealand

Genomic instability is a conserved factor in lifespan reduction, although the molecular mechanism is not known [1]. Studies in the yeast Saccharomyces cerevisiae over the past 20 years have found a connection between the ribosomal RNA gene cluster (rdna) and lifespan [2]. The highly repetitive rdna exhibits genomic instability, and the anti-aging histone deacetylase gene SIR2 regulates this instability. We previously proposed that SIR2 governs lifespan by repressing rdna noncoding transcription and rdna instability, but the extent to which lifespan is affected by SIR2 acting at the rdna versus other genomic regions, and the relationship between rdna noncoding transcription/rdna stability and lifespan have remained controversial. To control rdna noncoding transcription and rdna instability, we use a strain in which the rdna noncoding promoter is replaced with an inducible promoter. Here, we show that repression of noncoding transcription extends lifespan and makes SIR2 dispensable for lifespan extension. These results indicate that Sir2 maintains lifespan through repression of E-pro noncoding transcription in the rdna cluster, rather than pleiotropically at other loci. The observation of rdna instability in other organisms, including humans, suggests that this may be a conserved aging pathway.

关键词： CELL physiology YEAST PHYSIOLOGY RECOMBINANT dna non-coding dna HISTONE deacetylase GENOMICS

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FATHMM-XF: accurate prediction of pathogenic point mutations via extended features

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BIOINFORMATICS 2018年第3期34卷 511-513页

作者： Rogers, Mark F. Shihab, Hashem A. Mort, Matthew Cooper, David N. Gaunt, Tom R. Campbell, Colin Univ Bristol Intelligent Syst Lab Bristol BS8 1UB Avon England Univ Bristol MRC Integrat Epidemiol Unit IEU Bristol BS8 2BN Avon England Cardiff Univ Inst Med Genet Cardiff CF14 4XN Wales

aSummary: We present FATHMM-XF, a method for predicting pathogenic point mutations in the human genome. Drawing on an extensive feature set, FATHMM-XF outperforms competitors on benchmark tests, particularly in non-coding regions where the majority of pathogenic mutations are likely to be found. Availability and implementation: The FATHMM-XF web server is available at http://***/fathmm-xf/, and as tracks on the Genome Tolerance Browser: http://***. Predictions are provided for human genome version GRCh37/hg19. The data used for this project can be downloaded from: http://***/fathmm-xf/ Contact: mark. rogers@*** or ***@*** Supplementary information: Supplementary data are available at Bioinformatics online.

关键词： HUMAN genome MUTATION (Biology) PATHOGENIC microorganisms MICROBIAL genetics non-coding dna

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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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The role of codons during a natural selection

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CHEMICAL PHYSICS 2021年 540卷 110986-110986页

作者： Pincak, Richard Bartos, Erik Slovak Acad Sci Inst Expt Phys Watsonova 47 Kosice 04353 Slovakia Joint Inst Nucl Res Bogoliubov Lab Theoret Phys Dubna 141980 Moscow Region Russia Slovak Acad Sci Inst Phys Dubravska Cesta 9 Bratislava 84511 Slovakia

We suggest the origin of coded amino acids in nature by using a new theory on the connection in lattice Pascal's triangle and adding some properties of cohomology theory to biological objects as dna, RNA, and proteins. With the enhancement of the energy-momentum tensor equation for this new theory, we can better understand and explain a new role of codons with their symmetry in gene expression. For the investigation of codon interaction was used model of lattice Pascal's triangle. With this approach we proof the existence of twenty coded amino acids.

关键词： Connection Amino acid Retrotransposon non-coding dna Pascal's triangle

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Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome

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NEURAL PLASTICITY 2012年第2012期2012卷 104796-104796页

作者： Kelley, Karen Chang, Shin-Ju E. Lin, Shi-Lung WJWU & LYNN Inst Stem Cell Res Div Regenerat Med Santa Fe Springs CA 90670 USA

The majority of the human genome is comprised of non-coding dna, which frequently contains redundant microsatellite-like trinucleotide repeats. Many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs) such as fragile X syndrome (FXS). After transcription, the trinucleotide repeats can fold into RNA hairpins and are further processed by Dicer endoribonuclases to form microRNA (miRNA)-like molecules that are capable of triggering targeted gene-silencing effects in the TREDs. However, the function of these repeat-associated miRNAs (ramRNAs) is unclear. To solve this question, we identified the first native ramRNA in FXS and successfully developed a transgenic zebrafish model for studying its function. Our studies showed that ramRNA-induced dna methylation of the FMR1 5'-UTR CGG trinucleotide repeat expansion is responsible for both pathological and neurocognitive characteristics linked to the transcriptional FMR1 gene inactivation and the deficiency of its protein product FMRP. FMRP deficiency often causes synapse deformity in the neurons essential for cognition and memory activities, while FMR1 inactivation augments metabotropic glutamate receptor (mGluR)-activated long-term depression (LTD), leading to abnormal neuronal responses in FXS. Using this novel animal model, we may further dissect the etiological mechanisms of TREDs, with the hope of providing insights into new means for therapeutic intervention.

关键词： MICRORNA FRAGILE X syndrome HUMAN genome non-coding dna MICROSATELLITES (Genetics) TRINUCLEOTIDE repeats ANIMAL models in research

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A Statistical Framework to Predict Functional non-coding Regions in the Human Genome Through Integrated Analysis of Annotation Data

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SCIENTIFIC REPORTS 2015年第1期5卷 10576-10576页

作者： Lu, Qiongshi Hu, Yiming Sun, Jiehuan Cheng, Yuwei Cheung, Kei-Hoi Zhao, Hongyu Yale Univ Sch Publ Hlth Dept Biostat New Haven CT 06520 USA Yale Univ Program Computat Biol & Bioinformat New Haven CT USA Yale Univ Sch Med Yale Ctr Med Informat New Haven CT USA Yale Univ Sch Med Dept Emergency Med New Haven CT USA VA Connecticut Healthcare Syst West Haven CT USA

Identifying functional regions in the human genome is a major goal in human genetics. Great efforts have been made to functionally annotate the human genome either through computational predictions, such as genomic conservation, or high-throughput experiments, such as the ENCODE project. These efforts have resulted in a rich collection of functional annotation data of diverse types that need to be jointly analyzed for integrated interpretation and annotation. Here we present GenoCanyon, a whole-genome annotation method that performs unsupervised statistical learning using 22 computational and experimental annotations thereby inferring the functional potential of each position in the human genome. With GenoCanyon, we are able to predict many of the known functional regions. The ability of predicting functional regions as well as its generalizable statistical framework makes GenoCanyon a unique and powerful tool for whole-genome annotation. The GenoCanyon web server is available at http://***

关键词： HUMAN genome non-coding dna non-coding RNA GENE expression EXPECTATION-maximization algorithms

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Application of artificial intelligence for detection of chemico-biological interactions associated with oxidative stress and dna damage

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CHEMICO-BIOLOGICAL INTERACTIONS 2021年 345卷 109533-109533页

作者： Davidovic, Lazar M. Laketic, Darko Cumic, Jelena Jordanova, Elena Pantic, Igor Univ Belgrade Studentski Trg 1 RS-11000 Belgrade Serbia Univ Belgrade Fac Med Inst Anat Niko Miljanic Dr Subotica 4-2 RS-11129 Belgrade Serbia Univ Belgrade Fac Med Clin Ctr Serbia Dr Koste Todorov 8 RS-11129 Belgrade Serbia Univ Belgrade Clin Hosp Ctr Fac Med Vukova 9 RS-11000 Belgrade Serbia Univ Belgrade Fac Med Inst Med Physiol Lab Cellular Physiol Visegradska 26-2 RS-11129 Belgrade Serbia Univ Haifa 199 Abba Hushi Blvd Mt Carmel IL-3498838 Haifa Israel

In recent years, various AI-based methods have been developed in order to uncover chemico-biological interactions associated with dna damage and oxidative stress. Various decision trees, bayesian networks, random forests, logistic regression models, support vector machines as well as deep learning tools, have great potential in the area of molecular biology and toxicology, and it is estimated that in the future, they will greatly contribute to our understanding of molecular and cellular mechanisms associated with dna damage and repair. In this concise review, we discuss recent attempts to build machine learning tools for assessment of radiation - induced dna damage as well as algorithms that can analyze the data from the most frequently used dna damage assays in molecular biology. We also review recent works on the detection of antioxidant proteins with machine learning, and the use of AI-related methods for prediction and evaluation of noncoding dna sequences. Finally, we discuss previously published research on the potential application of machine learning tools in aging research.

关键词： Reactive oxygen species Radiation Machine learning non-coding dna Aging

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TRRUST: a reference database of human transcriptional regulatory interactions

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SCIENTIFIC REPORTS 2015年第1期5卷 11432-11432页

作者： Han, Heonjong Shim, Hongseok Shin, Donghyun Shim, Jung Eun Ko, Yunhee Shin, Junha Kim, Hanhae Cho, Ara Lee, Eiru Kim Tak Kim, Hyojin Kim, Kyungsoo Yang, Sunmo Bae, Dasom Yun, Ayoung Kim, Sunphil Kim, Chan Yeong Cho, Hyeon Jin Kang, Byunghee Shin, Susie Lee, Insuk Yonsei Univ Dept Biotechnol Coll Life Sci & Biotechnol Seoul 120749 South Korea

The reconstruction of transcriptional regulatory networks (TRNs) is a long-standing challenge in human genetics. Numerous computational methods have been developed to infer regulatory interactions between human transcriptional factors (TFs) and target genes from high-throughput data, and their performance evaluation requires gold-standard interactions. Here we present a database of literature-curated human TF-target interactions, TRRUST (transcriptional regulatory relationships unravelled by sentence-based text-mining, http://***/trrust), which currently contains 8,015 interactions between 748 TF genes and 1,975 non-TF genes. A sentence-based text-mining approach was employed for efficient manual curation of regulatory interactions from approximately 20 million Medline abstracts. To the best of our knowledge, TRRUST is the largest publicly available database of literature-curated human TF-target interactions to date. TRRUST also has several useful features: i) information about the mode-of-regulation;ii) tests for target modularity of a query TF;iii) tests for TF cooperativity of a query target;iv) inferences about cooperating TFs of a query TF;and v) prioritizing associated pathways and diseases with a query TF. We observed high enrichment of TF-target pairs in TRRUST for top-scored interactions inferred from high-throughput data, which suggests that TRRUST provides a reliable benchmark for the computational reconstruction of human TRNs.

关键词： GENE regulatory networks TRANSCRIPTION factors GENE targeting HUMAN genome non-coding dna GENETIC regulation

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Pleiotropic Enhancers are Ubiquitous Regulatory Elements in the Human Genome

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GENOME BIOLOGY AND EVOLUTION 2022年第6期14卷 evac071页

作者： Laiker, Ian Frankel, Nicolas Consejo Nacl Invest Cient & Tecn CONICET Inst Fisiol Biol Mol & Neurociencias IFIBYNE RA-1428 Buenos Aires DF Argentina Univ Buenos Aires UBA RA-1428 Buenos Aires DF Argentina Univ Buenos Aires UBA Fac Ciencias Exactas & Nat FCEN Dept Ecol Genet & Evoluc RA-1428 Buenos Aires DF Argentina

Enhancers are regulatory elements of genomes that determine spatio-temporal patterns of gene expression. The human genome contains a vast number of enhancers, which largely outnumber protein-coding genes. Historically, enhancers have been regarded as highly tissue-specific. However, recent evidence has demonstrated that many enhancers are pleiotropic, with activity in multiple developmental contexts. Yet, the extent and impact of pleiotropy remain largely unexplored. In this study we analyzed active enhancers across human organs based on the analysis of both eRNA transcription (FANTOM5 consortium data sets) and chromatin architecture (ENCODE consortium data sets). We show that pleiotropic enhancers are pervasive in the human genome and that most enhancers active in a particular organ are also active in other organs. In addition, our analysis suggests that the proportion of context-specific enhancers of a given organ is explained, at least in part, by the proportion of context-specific genes in that same organ. The notion that such a high proportion of human enhancers can be pleiotropic suggests that small regions of regulatory dna contain abundant regulatory information and that these regions evolve under important evolutionary constraints.

关键词： human genome non-coding dna gene regulation CRE enhancer pleiotropy

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