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100 Publications visible to you, out of a total of 100
Transcriptome-Guided Drug Repositioning.

Abstract (Expand)

Drug repositioning can save considerable time and resources and significantly speed up the drug development process. The increasing availability of drug action and disease-associated transcriptome data … makes it an attractive source for repositioning studies. Here, we have developed a transcriptome-guided approach for drug/biologics repositioning based on multi-layer self-organizing maps (ml-SOM). It allows for analyzing multiple transcriptome datasets by segmenting them into layers of drug action- and disease-associated transcriptome data. A comparison of expression changes in clusters of functionally related genes across the layers identifies "drug target" spots in disease layers and evaluates the repositioning possibility of a drug. The repositioning potential for two approved biologics drugs (infliximab and brodalumab) confirmed the drugs' action for approved diseases (ulcerative colitis and Crohn's disease for infliximab and psoriasis for brodalumab). We showed the potential efficacy of infliximab for the treatment of sarcoidosis, but not chronic obstructive pulmonary disease (COPD). Brodalumab failed to affect dysregulated functional gene clusters in Crohn's disease (CD) and systemic juvenile idiopathic arthritis (SJIA), clearly indicating that it may not be effective in the treatment of these diseases. In conclusion, ml-SOM offers a novel approach for transcriptome-guided drug repositioning that could be particularly useful for biologics drugs.

Authors: A. Arakelyan, L. Nersisyan, M. Nikoghosyan, S. Hakobyan, A. Simonyan, L. Hopp, H. Loeffler-Wirth, H. Binder

Date Published: 12th Dec 2019

Publication Type: Journal

Expression of micro-RNAs miR-31, miR-146a, miR-181c and miR-155 and their target gene IL-2 are altered in schizophrenia: a case-control study

Abstract (Expand)

Background: Schizophrenia is a severe psychiatric disorder with a heterogeneous clinical phenotype. The association of interleukins and other cytokines and their receptors with schizophrenia has been … previously reported. Additionally, a number of studies have reported altered mico-RNA (miRNA) expression in schizophrenia and other psychiatric disorders. The aim of our study was to explore the possible association of miR-31, miR-146a, miR-181c and miR-155 with schizophrenia pathogenesis, as well as their link to IL2 gene expression in disease. Methods: For this case-control study, 225 patients with paranoid schizophrenia and 225 sex- and age-matched controls with no family history of schizophrenia were recruited. The expression of studied miRNAs and the IL2 gene was measured using qPCR. DNA samples of all patients and controls were genotyped for IL2 rs2069778 single nucleotide polymorphism (SNP) using PCR with sequence specific primers (PCR-SSP). Statistical analyses include the Mann-Whitney U-test and Fischer’s exact test. Results: All studied miRNAs were over-expressed in schizophrenic patients IL2 gene expression was down-regulated in schizophrenic patients. The IL2 rs2069778 SNP is not associated with schizophrenia but regulates expression of the IL2 gene. Conclusions: Over-expression of studied miRNAs and down-regulation of IL2 gene expression may be considered as genetic risk factors for chronic schizophrenia. Abnormalities in studied miRNA expressions result in the deregulation of the T-cell receptor signaling pathway in schizophrenia.

Authors: Hovsep Ghazaryan, Roksana Zakharyan, Martin Petrek, Zdenka Navratilova, Andranik Chavushyan, Eva Novosadova, Arsen Arakelyan

Date Published: 10th Dec 2019

Publication Type: Journal

WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Abstract (Expand)

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, … however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother's, and, to a lesser extent, with father's TL having the strongest influence on the offspring. In this cohort, mother's, but not father's age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

Authors: Lilit Nersisyan, Maria Nikoghosyan, Laurent C. Francioli, Androniki Menelaou, Sara L. Pulit, Clara C. Elbers, Wigard P. Kloosterman, Jessica van Setten, Isaäc J. Nijman, Ivo Renkens, Paul I. W. de Bakker, Freerk van Dijk, Pieter B. T. Neerincx, Patrick Deelen, Alexandros Kanterakis, Martijn Dijkstra, Heorhiy Byelas, K. Joeri van der Velde, Mathieu Platteel, Morris A. Swertz, Cisca Wijmenga, Pier Francesco Palamara, Itsik Pe’er, Kai Ye, Eric-Wubbo Lameijer, Matthijs H. Moed, Marian Beekman, Anton J. M. de Craen, H. Eka D. Suchiman, P. Eline Slagboom, Victor Guryev, Abdel Abdellaoui, Jouke Jan Hottenga, Mathijs Kattenberg, Gonneke Willemsen, Dorret I. Boomsma, Elisabeth M. van Leeuwen, Lennart C. Karssen, Najaf Amin, Fernando Rivadeneira, Aaron Isaacs, Albert Hofman, André G. Uitterlinden, Cornelia M. van Duijn, Mannis van Oven, Manfred Kayser, Martijn Vermaat, Jeroen F. J. Laros, Johan T. den Dunnen, David van Enckevort, Hailiang Mei, Mingkun Li, Mark Stoneking, Barbera D. C. van Schaik, Jan Bot, Tobias Marschall, Alexander Schönhuth, Jayne Y. Hehir-Kwa, Robert E. Handsaker, Paz Polak, Mashaal Sohail, Dana Vuzman, Karol Estrada, Steven A. McCarroll, Shamil R. Sunyaev, Fereydoun Hormozdiari, Vyacheslav Koval, Carolina Medina-Gomez, Ben Oostra, Jan H. Veldink, Leonard H. van den Berg, Steven J. Pitts, Shobha Potluri, Purnima Sundar, David R. Cox, Peter de Knijff, Qibin Li, Yingrui Li, Yuanping Du, Ruoyan Chen, Hongzhi Cao, Jun Wang, Ning Li, Sujie Cao, Jasper A. Bovenberg, Gert-Jan B. van Ommen, Arsen Arakelyan

Date Published: 10th Dec 2019

Publication Type: Journal

Telomere Length Maintenance and Its Transcriptional Regulation in Lynch Syndrome and Sporadic Colorectal Carcinoma

Abstract (Expand)

Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution … of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development. Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the "classical" telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures. Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity. Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method. Keywords: DNAseq and RNAseq data analysis; colorectal cancer; mismatch repair; pathway models; telomerase and alternative telomere maintenance; telomere attrition; telomere length; telomere repeat variants.

Authors: Lilit Nersisyan, Lydia Hopp, Henry Loeffler-Wirth, Jörg Galle, Markus Loeffler, Arsen Arakelyan, Hans Binder

Date Published: 5th Nov 2019

Publication Type: Journal

Insights into matrilineal genetic structure, differentiation and ancestry of Armenians based on complete mitogenome data

Abstract (Expand)

Distinctive peculiarities of Armenians such as their millennia-long genetic isolation and strong national identity attract a keen interest while studying the demographic history of the West Asia. Here, … to examine their fine-scale matrilineal genetic structure, ancestry and relationships with neighboring populations, we analyzed 536 complete mitogenomes (141 of which are novel) from 8 geographically different Armenian populations, covering the whole stretch of historical Armenia. The observed patterns highlight a remarkable degree of matrilineal genetic heterogeneity and weak population structuring of Armenians. Moreover, our phylogeographic analysis reveals common ancestries for some mtDNA lineages shared by West Asians, Transcaucasians, Europeans, Central Asians and Armenians. About third of the mtDNA subhaplogroups found in Armenian gene pool might be considered as Armenian-specific, as these are virtually absent elsewhere in Europe, West Asia and Transcaucasia. Coalescence ages of most of these lineages do not exceed 3.1 kya and coincide well with the population size growth started around 1.8-2.8 kya detectable only in the Bayesian Skyline Plots based on the Armenian-specific mtDNA haplotypes.

Authors: Miroslava Derenko, Galina Denisova, Boris Malyarchuk, Anahit Hovhannisyan, Zaruhi Khachatryan, Peter Hrechdakian, Andrey Litvinov, Levon Yepiskoposyan

Date Published: 1st Aug 2019

Publication Type: Journal

Potential Involvement of Salmonella Infection in Autoimmunity

Abstract (Expand)

In this work, we investigated the potential effects of nontyphoidal Salmonella infection on autoantibody (AA) formation. The titer and profiles of autoantibodies in the sera of patients with acute … salmonellosis due to Salmonella enterica serovar Typhimurium (S. Typhimurium) or Salmonella enterica serovar Enteritidis (S. Enteritidis) infection, as well as in convalescent patients, were determined with indirect immunofluorescence. A significant increase of autoantibodies in acute diseases caused by both serotypes of Salmonella and during post infection by S. Enteritidis was detected. Antibody profile analysis by multivariate statistics revealed that this increase was non-specific and was not dependent on the infectious agent or disease stage. The results obtained suggest that nontyphoidal Salmonella infection contributes to the generation of autoantibodies and may play a role in autoimmune disease.

Authors: Zhanna Ktsoyan, Lyudmila Budaghyan, Marina Agababova, Armine Mnatsakanyan, Karine Arakelova, Zaruhi Gevorgyan, Anahit Sedrakyan, Alvard Hovhannisyan, Mkhitar Mkrtchyan, Magdalina Zakharyan, Arsen Arakelyan, Rustam Aminov

Date Published: 3rd Jul 2019

Publication Type: Journal

A modular transcriptome map of mature B cell lymphomas

Abstract (Expand)

Background: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic … phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. Conclusions: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities. Keywords: B cell malignancies; Gene regulation; Machine learning; Molecular subtypes; Tumor heterogeneity.

Authors: Henry Loeffler-Wirth, Markus Kreuz, Lydia Hopp, Arsen Arakelyan, Andrea Haake, Sergio B. Cogliatti, Alfred C. Feller, Martin-Leo Hansmann, Dido Lenze, Peter Möller, Hans Konrad Müller-Hermelink, Erik Fortenbacher, Edith Willscher, German Ott, Andreas Rosenwald, Christiane Pott, Carsten Schwaenen, Heiko Trautmann, Swen Wessendorf, Harald Stein, Monika Szczepanowski, Lorenz Trümper, Michael Hummel, Wolfram Klapper, Reiner Siebert, Markus Loeffler, Hans Binder

Date Published: 30th Apr 2019

Publication Type: Journal

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