DOCSLIB.ORG

NON CODING RNA: Geni Che Non Codificano Per Proteine Non-Coding Rnas (Ncrnas) Oltre Il 50% Dei Geni Non Codifica Per Proteine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
NON CODING RNA: Geni Che Non Codificano Per Proteine Non-Coding Rnas (Ncrnas) Oltre Il 50% Dei Geni Non Codifica Per Proteine Corso di Biologia Molecolare e Bioinformatica Prof. Caterina Missero 2° anno della Laurea Magistrale in Biologia Lezione 24 NON CODING RNA: Geni che non codificano per proteine Non-coding RNAs (ncRNAs) oltre il 50% dei geni non codifica per proteine: – RNA strutturali: • tRNA • rRNA • small nuclear RNAs • small nucleolar RNAs – RNA regolatori: • miRNA • siRNA • Long noncoding RNA (LincrRNA): >200 nucleotidi; intragenici o intergenici Genes in the human genome RNA-seq Long non coding RNA non hanno tutti il poly A Long noncoding RNA: LincRNA • Intergenici • intragenici/intronici • antisense • funzioni in cis (es. Xist) o in trans (es. Hotair) • Possono essere espressi in maniera tessuto specifica Per l’identificazione di questi ncRNA ci si e’ basati anche sulle modificazioni della cromatina che marcano i geni trascritti • lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths. • A striking bias toward two-exon transcripts • Predominantly localized in the chromatin and nucleus, and a fraction appear to be preferentially processed into small RNAs. • They are under stronger selective pressure than neutrally evolving sequences • lncRNAs are generally lower expressed than protein-coding genes and display more tissue-specific expression patterns. • Expression correlation analysis indicates that lncRNAs show particularly striking positive correlation with the expression of antisense coding genes. Are lncRNAs functional? Coding potential better distinguish not only between coding RNAs and ncRNAs, but also between small coding RNAs and small ncRNAs than the state-of-the-art methods due to the addition of the novel RNA features. A recent study proposes 1335 novel human coding RNAs from a large number of RNA-seq datasets. However, only 119 transcripts are predicted as coding RNAs by the CPPred. In fact, almost all proposed novel coding RNAs are ncRNAs (91.1%), which is consistent with previous reports. LncRNA sono meno espressi e meno ubiquitari Evolution, junk DNA and long non coding • Transcriptome studies reveal pervasive transcription of complex genomes, such as those of mammals. • Despite popular arguments for functionality of most, if not all, of these transcripts, genome-wide analysis of selective constraints indicates that most of the produced RNA are junk. However, junk is not garbage. On the contrary, junk transcripts provide the raw material for the evolution of diverse long non-coding (lnc) RNAs by non-adaptive mechanisms, such as constructive neutral evolution. • The generation of many novel functional entities, such as lncRNAs, that fuels organismal complexity does not seem to be driven by strong positive selection. Rather, the weak selection regime that dominates the evolution of most multicellular eukaryotes provides ample material for functional innovation with relatively little adaptation involved. Struttura e funzione dei LncRNA • Effettori piu’ semplici e versatili delle proteine (possono associarsi a diversi ligandi, ed ad acidi nucleici semplicemente per appaiamento) • La produzione a livello cellulare e’ piu’ semplice, non richiede apparato di traduzione e degradazione delle proteine • Piu’ tolleranti alle mutazioni, e meno conservati • Localizzazione nucleare o citoplasmatica A regulatory RNA gene can transition faster from being transcriptionally inactive to fully functional Ciclo dei long non-coding RNA Ciclo dei coding RNA RNA can fold into complex three-dimensional structures that can specifically bind various ligands As conformational changes can be triggered by ligand binding, RNA structures themselves can be very dynamic RNA is a biochemically versatile polymer Ability to base pair with other nucleic acids: recognizing both RNA and DNA targets through simple one-to-one base pairing interactions (less complicated than for a protein!) Long non-coding RNAs as scaffolds LncRNA– protein interactions can have various functions, including: 1) combining the functions of multiple proteins 2) localizing complexes to genomic DNA 3) modifying the structure of proteins 4) competitively inhibiting protein function (as decoys) 5) providing a multivalent platform, for example, to increase the avidity of protein interactions or to promote RNA– protein complex polymerization. A) lncRNAs can act as guides to target chromatin-modifying complexes to specific genomic locations for the regulation of gene expression. B) lncRNAs can act as dynamic scaffolds for cofactors to transiently assemble together. C) lncRNAs can bind to microRNAs or transcription factors as decoys to sequester them away from their targets, affecting transcription and translation. Funzioni dei lncRNAs • Regolazione della trascrizione • Regolazione del processamento del mRNA • Modulazione del controllo post-trascrizionale • Regolatori dell’attivita’ di una proteina • Scaffold per macro-complessi • Molecole di segnalazione RNA are less restricted in terms of their conservation and more tolerant of mutations RNA interactome analysis (RIA-seq) RIA-seq identifies lncRNA-interacting RNAs Schematic representation of high-throughput assays to analyze the lncRNA RNA- interactome Protein interactome analysis Schematic representation of protein-interactome. Left panel: Protein microarray assay. Right panel: RNA-binding protein pulldown Regolazione della trascrizione (I) LncRNA partecipano a complessi di modificazione della cromatina e contribuiscono al targeting di specifici locus genici EXAMPLES: HOTAIR which functions in trans to direct the chromatin modifier Polycomb Repressive Complex 2 (PRC2) to the developmental HOXD locus and, when aberrantly overexpressed, to cancer-related genes, leading to gene repression XIST TSIX lncRNAs can bind one or more chromatin-modifying complexes and target their activities to specific DNA loci. Depending on the nature of the enzymes bound, lncRNA-mediated chromatin modifications can activate or repress gene expression Regolazione post-trascrizionale (VI) decoys to attenuate small RNA regulation Linear or circular lncRNAs can function as miRNA decoy to sequester miRNAs from their target mRNAs Circular RNAs • observed for decades in eukaryotic cells but perceived as splicing errors • discovery of their abundance in high-throughput deep sequencing: very abundant and highly expressed • circular RNAs are distinct from their linear counterparts because they are devoid of the terminal structures (e.g., 5’ cap or a polyA tail) Circular RNAs • because of the lack of free ends, circular RNAs are resistant toward exonucleases, thereby escaping normal RNA turnover • generated co-transcriptionally at the expense of canonical linear mRNA Biogenesis of circular RNAs • generated during splicing through various mechanisms • splicing with a strong dependence on intronic sequences • exon circularization depends on flanking intronic complementary sequences • Splice sites along with short (~30- to 40- nucleotide) inverted repeats, such as Alu elements, are sufficient to allow the intervening exons to circularize in cells • complementary repetitive intronic sequences (e.g., Alu-sequences) favor back-splicing during RNA maturation L’esone 2 e 3 sono fiancheggiati da sequenze Alu Localizzazione sequenze Alu nel nucleo di fibroblasti Alu elements are primate-specific repeats and comprise 11% of the human genome. They have wide-ranging influences on gene expression. Alu elements are the most abundant transposable elements. Alu elements are about 300 base pairs long and are therefore classified as short interspersed nuclear elements (SINEs) among the class of repetitive DNA elements. Localization of Alu Sequences in Nuclei of Fibroblasts and Lymphocytes Alu (porzioni in verde): sequenze ripetute ricche in GC, sono piu’ presenti in zone trascritte Bolzer A, Kreth G, Solovei I, Koehler D, et al. (2005) Three-Dimensional Maps of All Chromosomes in Human Male Fibroblast Nuclei and Prometaphase Rosettes. PLoS Biol 3(5): e157. doi:10.1371/journal.pbio.0030157 Circular RNAs • exon circularization and linear splicing compete with each other in a tissue-specific fashion • several types of circular RNA transcripts can be produced from a single gene • precursor messenger RNA (pre-mRNA) splicing machinery ‘‘backsplices’’ and covalently joins, for example, the two ends of a single exon. Proactive back-splice event The biogenesis of circRNAs is instead actively regulated and favored by the presence of specific and repetitive sequences’ and RNA-binding proteins’(RBPs) binding sites within the introns up- and downstream of the circularizing exons the 3’ tail of one exon is joined to the 5’ head of an upstream exon Pseudogeni • Si pensava fossero copie non funzionali di geni • Si originano per: – duplicazione: non-processati – retrotrasposizione: processati, reinseriti nel genoma via RNA (introni, e polyA) • Possono essere trascritti, ma non tradotti Interessanti dal punto di vista evolutivo Pier Paolo Pandolfi • Long ncRNAs can function as miRNA decoys, also referred to as target mimics or sponges, in which long ncRNAs carry a short stretch of sequence sharing homology to miRNA-binding sites in endogenous targets. • As a consequence, miRNA decoys are able to sequester and inactivate miRNA function. PTEN: TUMOR SUPPRESSOR GENE The loss and mutation of PTEN in various cancers lead to hyperactive PI3K signaling. PTEN AND CANCER • Monoallelic mutation of PTEN in early cancer • Loss or mutation of the second allele advanced cancers • Cells are sensitive to even subtle
Load more

Recommended publications
  • Database Tool Pseudomap: an Innovative and Comprehensive Resource for Identification of Sirna-Mediated Mechanisms in Human Trans
    Database, Vol. 2013, Article ID bat001, doi:10.1093/database/bat001 ............................................................................................................................................................................................................................................................................................. Database tool pseudoMap: an innovative and comprehensive resource for identification of siRNA-mediated mechanisms in human Downloaded from transcribed pseudogenes Wen-Ling Chan1,2, Wen-Kuang Yang3,4, Hsien-Da Huang1,2,* and Jan-Gowth Chang5,6,7,* http://database.oxfordjournals.org/ 1Institute of Bioinformatics and Systems Biology, 2Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, 3Cell/Gene Therapy Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, 4Departments of Biochemistry and Medicine, China Medical University, Taichung, 5Center of RNA Biology and Clinical Application, 6Department of Laboratory Medicine, China Medical University Hospital, Taichung, and 7School of Medicine, China Medical University, Taichung, Taiwan *Corresponding author: Tel: +886 4 22052121 ext. 2008; Email: [email protected]; Fax: +886 4 22031029 Correspondence may also be addressed to Hsien-Da Huang, Tel: +886 3 5712121 ext. 56957; Email: [email protected]; Fax: +886 3 5739320 Submitted 31 October 2012; Revised 1 January 2013; Accepted 3 January 2013 Citation details: Chan,W.-L., Yang,W.-K., Huang,H.-D. et al. pseudoMap:
    [Show full text]
  • Disruption of YY1-EZH2 Interaction Using Synthetic Peptides Inhibits Breast Cancer Development
    cancers Article Disruption of YY1-EZH2 Interaction Using Synthetic Peptides Inhibits Breast Cancer Development Cheng Yi 1, Guangyue Li 1, Wenmeng Wang 1, Yixuan Sun 1, Yueling Zhang 2, Chen Zhong 3, Daniel B. Stovall 4, Dangdang Li 1, Jinming Shi 1,* and Guangchao Sui 1,* 1 Key Laboratory of Saline-Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin 150040, China; [email protected] (C.Y.); [email protected] (G.L.); [email protected] (W.W.); [email protected] (Y.S.); [email protected] (D.L.) 2 State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China; [email protected] 3 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China; [email protected] 4 College of Arts and Sciences, Winthrop University, Rock Hill, SC 29733, USA; [email protected] * Correspondence: [email protected] (J.S.); [email protected] (G.S.); Tel.: +86-451-82191081 (J.S. & G.S.) Simple Summary: Both Yin Yang 1 (YY1) and enhancer of zeste homolog 2 (EZH2) are oncogenes with overexpressed statuses in cancers. As a transcription factor, YY1 recruits EZH2 through its oncoprotein binding (OPB) domain to repress gene expression. In this study, we identified the interaction domain of YY1 on EZH2 protein with amino acids 493–519, named the YY1 protein binding (YPB) domain. Synthetic peptides using YPB and OPB domain sequences effectively blocked endogenous YY1-EZH2 interaction. Functionally, YPB and OPB peptides could efficiently inhibit the Citation: Yi, C.; Li, G.; Wang, W.; proliferation of breast cancer cells, promote their apoptosis, and reduce tumor growth in a xenograft Sun, Y.; Zhang, Y.; Zhong, C.; Stovall, mouse model.
    [Show full text]
  • Microrna-Mediated Networks Underlie Immune Response Regulation in Papillary Thyroid 51
    OPEN MicroRNA-mediated networks underlie SUBJECT AREAS: immune response regulation in papillary GENE REGULATORY NETWORKS thyroid carcinoma CANCER GENOMICS Chen-Tsung Huang1, Yen-Jen Oyang1, Hsuan-Cheng Huang4 & Hsueh-Fen Juan1,2,3 Received 1 2 15 July 2014 Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan, Department of Life Science, National Taiwan University, Taipei, Taiwan, 3Institute of Molecular and Cellular Biology, National Taiwan University, Accepted Taipei, Taiwan, 4Institute of Biomedical Informatics and Center for Systems and Synthetic Biology, National Yang-Ming University, 9 September 2014 Taipei, Taiwan. Published 29 September 2014 Papillary thyroid carcinoma (PTC) is a common endocrine malignancy with low death rate but increased incidence and recurrence in recent years. MicroRNAs (miRNAs) are small non-coding RNAs with diverse regulatory capacities in eukaryotes and have been frequently implied in human cancer. Despite current Correspondence and progress, however, a panoramic overview concerning miRNA regulatory networks in PTC is still lacking. requests for materials Here, we analyzed the expression datasets of PTC from The Cancer Genome Atlas (TCGA) Data Portal and demonstrate for the first time that immune responses are significantly enriched and under specific should be addressed to regulation in the direct miRNA2target network among distinctive PTC variants to different extents. H.C.H. (hsuancheng@ Additionally, considering the unconventional properties of miRNAs, we explore the protein-coding ym.edu.tw) or H.F.J. competing endogenous RNA (ceRNA) and the modulatory networks in PTC and unexpectedly disclose ([email protected]) concerted regulation of immune responses from these networks. Interestingly, miRNAs from these conventional and unconventional networks share general similarities and differences but tend to be disparate as regulatory activities increase, coordinately tuning the immune responses that in part account for PTC tumor biology.
    [Show full text]
  • Database Tool Pseudomap: an Innovative and Comprehensive Resource for Identification of Sirna-Mediated Mechanisms in Human Transcribed Pseudogenes
    Database, Vol. 2013, Article ID bat001, doi:10.1093/database/bat001 ............................................................................................................................................................................................................................................................................................. Database tool pseudoMap: an innovative and comprehensive resource for identification of siRNA-mediated mechanisms in human transcribed pseudogenes Wen-Ling Chan1,2, Wen-Kuang Yang3,4, Hsien-Da Huang1,2,* and Jan-Gowth Chang5,6,7,* 1Institute of Bioinformatics and Systems Biology, 2Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, 3Cell/Gene Therapy Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, 4Departments of Biochemistry and Medicine, China Medical University, Taichung, 5Center of RNA Biology and Clinical Application, 6Department of Laboratory Medicine, China Medical University Hospital, Taichung, and 7School of Medicine, China Medical University, Taichung, Taiwan *Corresponding author: Tel: +886 4 22052121 ext. 2008; Email: [email protected]; Fax: +886 4 22031029 Correspondence may also be addressed to Hsien-Da Huang, Tel: +886 3 5712121 ext. 56957; Email: [email protected]; Fax: +886 3 5739320 Submitted 31 October 2012; Revised 1 January 2013; Accepted 3 January 2013 Citation details: Chan,W.-L., Yang,W.-K., Huang,H.-D. et al. pseudoMap: an innovative and comprehensive resource for identification
    [Show full text]
  • Comprehensive Biological Information Analysis of PTEN Gene in Pan-Cancer
    Comprehensive biological information analysis of PTEN gene in pan-cancer Hang Zhang Shanghai Medical University: Fudan University https://orcid.org/0000-0002-5853-7754 Wenhan Zhou Shanghai Medical University: Fudan University Xiaoyi Yang Shanghai Jiao Tong University School of Medicine Shuzhan Wen Shanghai Medical University: Fudan University Baicheng Zhao Shanghai Medical University: Fudan University Jiale Feng Shanghai Medical University: Fudan University Shuying Chen ( [email protected] ) https://orcid.org/0000-0002-9215-9777 Primary research Keywords: PTEN, correlated genes, TCGA, GEPIA, UALCAN, GTEx, expression, cancer Posted Date: April 12th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-388887/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/21 Abstract Background PTEN is a multifunctional tumor suppressor gene mutating at high frequency in a variety of cancers. However, its expression in pan-cancer, correlated genes, survival prognosis, and regulatory pathways are not completely described. Here, we aimed to conduct a comprehensive analysis from the above perspectives in order to provide reference for clinical application. Methods we studied the expression levels in cancers by using data from TCGA and GTEx database. Obtain expression box plot from UALCAN database. Perform mutation analysis on the cBioportal website. Obtain correlation genes on the GEPIA website. Construct protein network and perform KEGG and GO enrichment analysis on the STRING database. Perform prognostic analysis on the Kaplan-Meier Plotter website. We also performed transcription factor prediction on the PROMO database and performed RNA-RNA association and RNA-protein interaction on the RNAup Web server and RPISEq.
    [Show full text]
  • Pseudogenes: Pseudo-Functional Or Key Regulators in Health and Disease?
    Downloaded from rnajournal.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Pseudogenes: Pseudo-functional or key regulators in health and disease? RYAN CHARLES PINK, KATE WICKS, DANIEL PAUL CALEY, EMMA KATHLEEN PUNCH, LAURA JACOBS, and DAVID RAUL FRANCISCO CARTER School of Life Sciences, Oxford Brookes University, Headington, Oxford, OX3 0BP, United Kingdom ABSTRACT Pseudogenes have long been labeled as ‘‘junk’’ DNA, failed copies of genes that arise during the evolution of genomes. However, recent results are challenging this moniker; indeed, some pseudogenes appear to harbor the potential to regulate their protein-coding cousins. Far from being silent relics, many pseudogenes are transcribed into RNA, some exhibiting a tissue- specific pattern of activation. Pseudogene transcripts can be processed into short interfering RNAs that regulate coding genes through the RNAi pathway. In another remarkable discovery, it has been shown that pseudogenes are capable of regulating tumor suppressors and oncogenes by acting as microRNA decoys. The finding that pseudogenes are often deregulated during cancer progression warrants further investigation into the true extent of pseudogene function. In this review, we describe the ways in which pseudogenes exert their effect on coding genes and explore the role of pseudogenes in the increasingly complex web of noncoding RNA that contributes to normal cellular regulation. Keywords: pseudogenes; functional; noncoding RNA; transcription; RNA INTRODUCTION transcription or translation of the gene (Fig. 1A) result in the formation of ‘‘unitary’’ pseudogene (Zhang et al. 2010). The human genome, like that of other mammals, is littered Duplicated pseudogenes are created via tandem duplication with a variety of repetitive elements and noncoding genes.
    [Show full text]
  • PTENP1 Is a Cerna for PTEN
    Vitiello et al. Journal of Hematology & Oncology (2020) 13:73 https://doi.org/10.1186/s13045-020-00894-2 RAPID COMMUNICATION Open Access PTENP1 is a ceRNA for PTEN:it’s CRISPR clear Marianna Vitiello1,2, Monica Evangelista2, Yang Zhang3, Leonardo Salmena4,5, Pier Paolo Pandolfi3,6,7* and Laura Poliseno1,2* Abstract Here we apply state-of-the-art CRISPR technologies to study the impact that PTENP1 pseudogene transcript has on the expression levels of its parental gene PTEN, and hence on the output of AKT signaling in cancer. Our data expand the repertoire of approaches that can be used to dissect competing endogenous RNA (ceRNA)-based interactions, while providing further experimental evidence in support of the very first one that we discovered. Keywords: PTENP1, PTEN, ceRNA, CRISPR, CasRx-mediated knock-down, Cas9-mediated knock-in Main text Subsequent to our 2010 publication, many studies in- In our 2010 paper entitled “A coding independent func- dependently confirmed PTENP1 pseudogene as a ceRNA tion of gene and pseudogene mRNAs regulates tumor for PTEN in prostate cancer, in other cancer types (e.g., biology”, we provided the first evidence that RNA mole- bladder cancer, breast cancer, clear cell renal cell carcin- cules, including non-coding RNAs (such as pseudogenes) oma, endometrial carcinoma, gastric cancer, head and and mRNAs, may be endowed with a biological function neck squamous cell carcinoma, hepatocellular carcin- that specifically relies on their ability to compete for oma), and in other physio-pathological conditions (see microRNA binding [1]. Supplementary references for a list). Nonetheless, a Our findings have contributed to an evolving number of articles published in prestigious journals have microRNA-RNA interaction paradigm, where RNAs are repeatedly raised concerns about this functional inter- not only “passive” targets of microRNAs, but also “active” action.
    [Show full text]
  • Meta-Analysis of Prostate Cancer Gene Expression Data Identifies a Novel Discriminatory Signature Enriched for Glycosylating
    Barfeld et al. BMC Medical Genomics (2014) 7:513 DOI 10.1186/s12920-014-0074-9 RESEARCH ARTICLE Open Access Meta-analysis of prostate cancer gene expression data identifies a novel discriminatory signature enriched for glycosylating enzymes Stefan J Barfeld2*, Philip East1, Verena Zuber2 and Ian G Mills2,3* Abstract Background: Tumorigenesis is characterised by changes in transcriptional control. Extensive transcript expression data have been acquired over the last decade and used to classify prostate cancers. Prostate cancer is, however, a heterogeneous multifocal cancer and this poses challenges in identifying robust transcript biomarkers. Methods: In this study, we have undertaken a meta-analysis of publicly available transcriptomic data spanning datasets and technologies from the last decade and encompassing laser capture microdissected and macrodissected sample sets. Results: We identified a 33 gene signature that can discriminate between benign tissue controls and localised prostate cancers irrespective of detection platform or dissection status. These genes were significantly overexpressed in localised prostate cancer versus benign tissue in at least three datasets within the Oncomine Compendium of Expression Array Data. In addition, they were also overexpressed in a recent exon-array dataset as well a prostate cancer RNA-seq dataset generated as part of the The Cancer Genomics Atlas (TCGA) initiative. Biologically, glycosylation was the single enriched process associated with this 33 gene signature, encompassing four glycosylating enzymes. We went on to evaluate the performance of this signature against three individual markers of prostate cancer, v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) expression, prostate specific antigen (PSA) expression and androgen receptor (AR) expression in an additional independent dataset.
    [Show full text]
  • Epigenome Alterations in Aortic Valve Stenosis and Its Related Left
    Gošev et al. Clinical Epigenetics (2017) 9:106 DOI 10.1186/s13148-017-0406-7 REVIEW Open Access Epigenome alterations in aortic valve stenosis and its related left ventricular hypertrophy Igor Gošev1, Martina Zeljko2, Željko Đurić3, Ivana Nikolić4, Milorad Gošev5, Sanja Ivčević6, Dino Bešić7, Zoran Legčević7 and Frane Paić7* Abstract Aortic valve stenosis is the most common cardiac valve disease, and with current trends in the population demographics, its prevalence is likely to rise, thus posing a major health and economic burden facing the worldwide societies. Over the past decade, it has become more than clear that our traditional genetic views do not sufficiently explain the well-known link between AS, proatherogenic risk factors, flow-induced mechanical forces, and disease-prone environmental influences. Recent breakthroughs in the field of epigenetics offer us a new perspective on gene regulation, which has broadened our perspective on etiology of aortic stenosis and other aortic valve diseases. Since all known epigenetic marks are potentially reversible this perspective is especially exciting given the potential for development of successful and non-invasive therapeutic intervention and reprogramming of cells at the epigenetic level even in the early stages of disease progression. This review will examine the known relationships between four major epigenetic mechanisms: DNA methylation, posttranslational histone modification, ATP-dependent chromatin remodeling, and non-coding regulatory RNAs, and initiation and progression of AS. Numerous profiling and functional studies indicate that they could contribute to endothelial dysfunctions, disease-prone activation of monocyte-macrophage and circulatory osteoprogenitor cells and activation and osteogenic transdifferentiation of aortic valve interstitial cells, thus leading to valvular inflammation, fibrosis, and calcification, and to pressure overload-induced maladaptive myocardial remodeling and left ventricular hypertrophy.
    [Show full text]
  • Secondary Structural Model of MALAT1 Becomes Unstructured in Chronic Myeloid Leukemia and Undergoes Structural Rearrangement in Cervical Cancer
    non-coding RNA Hypothesis Secondary Structural Model of MALAT1 Becomes Unstructured in Chronic Myeloid Leukemia and Undergoes Structural Rearrangement in Cervical Cancer Matthew C. Wang , Phillip J. McCown † , Grace E. Schiefelbein and Jessica A. Brown * Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; [email protected] (M.C.W.); [email protected] (P.J.M.); [email protected] (G.E.S.) * Correspondence: [email protected] † Present address: Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA. Abstract: Long noncoding RNAs (lncRNAs) influence cellular function through binding events that often depend on the lncRNA secondary structure. One such lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), is upregulated in many cancer types and has a myriad of protein- and miRNA-binding sites. Recently, a secondary structural model of MALAT1 in noncancer- ous cells was proposed to form 194 hairpins and 13 pseudoknots. That study postulated that, in cancer cells, the MALAT1 structure likely varies, thereby influencing cancer progression. This work analyzes how that structural model is expected to change in K562 cells, which originated from a patient with chronic myeloid leukemia (CML), and in HeLa cells, which originated from a patient with cervical cancer. Dimethyl sulfate-sequencing (DMS-Seq) data from K562 cells and psoralen analysis of RNA interactions and structure (PARIS) data from HeLa cells were compared to the working structural model of MALAT1 in noncancerous cells to identify sites that likely undergo Citation: Wang, M.C.; McCown, P.J.; structural alterations. MALAT1 in K562 cells is predicted to become more unstructured, with almost Schiefelbein, G.E.; Brown, J.A.
    [Show full text]
  • Long Non-Coding Rnas and Micrornas in Endocrine-Related Cancers
    25 4 Endocrine-Related C M Klinge lncRNAs and miRNAs in 25:4 R259–R282 Cancer endocrine-related cancers REVIEW Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers Carolyn M Klinge Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA Correspondence should be addressed to C M Klinge: [email protected] Abstract The human genome is ‘pervasively transcribed’ leading to a complex array of non- Key Words coding RNAs (ncRNAs) that far outnumber coding mRNAs. ncRNAs have regulatory roles f miRNA in transcription and post-transcriptional processes as well numerous cellular functions f lncRNA that remain to be fully described. Best characterized of the ‘expanding universe’ of f ncRNA ncRNAs are the ~22 nucleotide microRNAs (miRNAs) that base-pair to target mRNA’s f transcription 3′ untranslated region within the RNA-induced silencing complex (RISC) and block f translation translation and may stimulate mRNA transcript degradation. Long non-coding RNAs (lncRNAs) are classified as >200 nucleotides in length, but range up to several kb and are heterogeneous in genomic origin and function. lncRNAs fold into structures that interact with DNA, RNA and proteins to regulate chromatin dynamics, protein complex assembly, transcription, telomere biology and splicing. Some lncRNAs act as sponges for miRNAs and decoys for proteins. Nuclear-encoded lncRNAs can be taken up by mitochondria and lncRNAs are transcribed from mtDNA. Both miRNAs and lncRNAs are dysregulated in endocrine cancers. This review provides an overview on the current understanding of the regulation and function of selected lncRNAs and miRNAs, and their interaction, in Endocrine-Related Cancer endocrine-related cancers: breast, prostate, endometrial and thyroid.
    [Show full text]
  • The Molecular Dynamics of Long Noncoding RNA Control of Transcription in PTEN and Its Pseudogene
    The molecular dynamics of long noncoding RNA control of transcription in PTEN and its pseudogene Nicholas Listera,1, Galina Shevchenkob,1, James L. Walshec, Jessica Groena, Per Johnssond, Linda Vidarsdóttire, Dan Grandere, Sandro F. Ataidec, and Kevin V. Morrisb,2 aThe University of New South Wales, Biotechnology and Biomedical Sciences, Sydney, NSW 2052, Australia; bCenter for Gene Therapy, City of Hope–Beckman Research Institute at the City of Hope, Duarte, CA 91010; cSchool of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia; dDepartment of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, 171 65 Stockholm, Sweden; and eDepartment of Oncology-Pathology, Cancer Center Karolinska, R8:03, Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden Edited by Jeannie T. Lee, Harvard Medical School Massachusetts General Hospital, Boston, MA, and approved August 2, 2017 (received for review January 4, 2017) RNA has been found to interact with chromatin and modulate that this RNA can target the PTEN promoter in the absence gene transcription. In human cells, little is known about how long of DNMT3a. noncoding RNAs (lncRNAs) interact with target loci in the context of chromatin. We find here, using the phosphatase and tensin Results homolog (PTEN) pseudogene as a model system, that antisense Detection and Function of 5′ UTR PTEN Promoter Transcripts. Pre- lncRNAs interact first with a 5′ UTR-containing promoter-spanning vious studies with small noncoding RNAs (ncRNAs) demon- transcript, which is then followed by the recruitment of DNA strated that an expressed low-copy transcript spanning the 5′ methyltransferase 3a (DNMT3a), ultimately resulting in the tran- UTR of protein coding genes, designated a promoter-associated scriptional and epigenetic control of gene expression.
    [Show full text]