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79 Publications visible to you, out of a total of 79
Genewise detection of variants in MEFV gene using nanopore sequencing

Abstract (Expand)

Mediterranean Fever (FMF) is a genetic disorder with complex inheritance patterns and genotype-phenotype associations, and it is highly prevalent in Armenia. FMF typically follows an autosomal recessive … inheritance pattern (OMIM: 249100), though it can occasionally display a rare dominant inheritance pattern with variable penetrance (OMIM։134610). The disease is caused by mutations in the MEFV gene, which encodes the pyrin protein. While the 26 most prevalent mutations account for nearly 99% of all FMF cases, more than 60 pathogenic mutations have been identified. In this study, we aimed to develop an affordable nanopore sequencing method for full-length MEFV gene mutation detection to aid in the diagnosis and screening of FMF. We employed a multiplex amplicon sequencing approach, allowing for the processing of up to 12 samples on both Flow cells and Flongle flow cells. The results demonstrated near-complete concordance between nanopore variant calling and qPCR genotypes. Moreover, nanopore sequencing identified additional variants, which were confirmed by whole exome sequencing. Additionally, intronic and UTR variants were detected. Our findings demonstrate the feasibility of full-gene nanopore sequencing for detecting FMF-associated pathogenic variants. The method is cost-effective, with costs comparable to those of the qPCR test, making it particularly suitable for settings with limited laboratory infrastructure. Further clinical validation using larger sample cohorts will be necessary.

Authors: Lilit Ghukasyan, Gisane Khachatryan, Tamara Sirunyan, Arpine Minasyan, Siras Hakobyan, Andranik Chavushyan, Varduhi Hayrapetyan, Hovsep Ghazaryan, Gevorg Martirosyan, Gohar Mkrtchyan, Valentina Vardanyan, Vahan Mukuchyan, Ashot Davidyants, Roksana Zakharyan, Arsen Arakelyan

Date Published: 29th Nov 2024

Publication Type: Journal

Pan-cancer analysis of telomere maintenance mechanisms.

Abstract (Expand)

Telomeres, protective caps at chromosome ends, maintain genomic stability and control cell lifespan. Dysregulated telomere maintenance mechanisms (TMMs) are cancer hallmarks, enabling unchecked cell … proliferation. We conducted a pan-cancer evaluation of TMM using RNA sequencing data from The Cancer Genome Atlas for 33 different cancer types and analyzed the activities of telomerase-dependent (TEL) and alternative lengthening of telomeres (ALT) TMM pathways in detail. To further characterize the TMM profiles, we categorized the tumors based on their ALT and TEL TMM pathway activities into five major phenotypes: ALT (high) TEL (low), ALT (low) TEL (low), ALT (middle) TEL (middle), ALT (high) TEL (high), and ALT (low) TEL (high). These phenotypes refer to variations in telomere maintenance strategies, shedding light on the heterogeneous nature of telomere regulation in cancer. Moreover, we investigated the clinical implications of TMM phenotypes by examining their associations with clinical characteristics and patient outcomes. Specific TMM profiles were linked to specific survival patterns, emphasizing the potential of TMM profiling as a prognostic indicator and aiding in personalized cancer treatment strategies. Gene ontology analysis of the TMM phenotypes unveiled enriched biological processes associated with cell cycle regulation (both TEL and ALT), DNA replication (TEL), and chromosome dynamics (ALT) showing that telomere maintenance is tightly intertwined with cellular processes governing proliferation and genomic stability. Overall, our study provides an overview of the complexity of transcriptional regulation of telomere maintenance mechanisms in cancer.

Authors: M. Hakobyan, H. Binder, A. Arakelyan

Date Published: 2nd Jul 2024

Publication Type: Journal

Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells

Abstract (Expand)

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer … between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.

Authors: Munevver Cinar, Lourdes Martinez-Medina, Pavan K Puvvula, Arsen Arakelyan, Badri N Vardarajan, Neil Anthony, Ganji P Nagaraju, Dongkyoo Park, Lei Feng, Faith Sheff, Marina Mosunjac, Debra Saxe, Steven Flygare, Olatunji B Alese, Jonathan L Kaufman, Sagar Lonial, Juan M Sarmiento, Izidore S Lossos, Paula M Vertino, Jose A Lopez, Bassel El-Rayes, Leon Bernal-Mizrachi

Date Published: 23rd May 2024

Publication Type: Journal

Temporal changes of gene expression in health, schizophrenia, bipolar disorder, and major depressive disorder.

Abstract (Expand)

The molecular events underlying the development, manifestation, and course of schizophrenia, bipolar disorder, and major depressive disorder span from embryonic life to advanced age. However, little … is known about the early dynamics of gene expression in these disorders due to their relatively late manifestation. To address this, we conducted a secondary analysis of post-mortem prefrontal cortex datasets using bioinformatics and machine learning techniques to identify differentially expressed gene modules associated with aging and the diseases, determine their time-perturbation points, and assess enrichment with expression quantitative trait loci (eQTL) genes. Our findings revealed early, mid, and late deregulation of expression of functional gene modules involved in neurodevelopment, plasticity, homeostasis, and immune response. This supports the hypothesis that multiple hits throughout life contribute to disease manifestation rather than a single early-life event. Moreover, the time-perturbed functional gene modules were associated with genetic loci affecting gene expression, highlighting the role of genetic factors in gene expression dynamics and the development of disease phenotypes. Our findings emphasize the importance of investigating time-dependent perturbations in gene expression before the age of onset in elucidating the molecular mechanisms of psychiatric disorders.

Authors: A. Arakelyan, S. Avagyan, A. Kurnosov, T. Mkrtchyan, G. Mkrtchyan, R. Zakharyan, K. R. Mayilyan, H. Binder

Date Published: 17th Feb 2024

Publication Type: Journal

Temporal changes of gene expression in health, schizophrenia, bipolar disorder, and major depressive disorder

Abstract (Expand)

The molecular events underlying the development, manifestation, and course of schizophrenia, bipolar disorder, and major depressive disorder span from embryonic life to advanced age. However, little … is known about the early dynamics of gene expression in these disorders due to their relatively late manifestation. To address this, we conducted a secondary analysis of post-mortem prefrontal cortex datasets using bioinformatics and machine learning techniques to identify differentially expressed gene modules associated with aging and the diseases, determine their time-perturbation points, and assess enrichment with expression quantitative trait loci (eQTL) genes. Our findings revealed early, mid, and late deregulation of expression of functional gene modules involved in neurodevelopment, plasticity, homeostasis, and immune response. This supports the hypothesis that multiple hits throughout life contribute to disease manifestation rather than a single early-life event. Moreover, the time-perturbed functional gene modules were associated with genetic loci affecting gene expression, highlighting the role of genetic factors in gene expression dynamics and the development of disease phenotypes. Our findings emphasize the importance of investigating time-dependent perturbations in gene expression before the age of onset in elucidating the molecular mechanisms of psychiatric disorders.

Authors: Arsen Arakelyan, Susanna Avagyan, Aleksey Kurnosov, Tigran Mkrtchyan, Gohar Mkrtchyan, Roksana Zakharyan, Karine R. Mayilyan, Hans Binder

Date Published: 17th Feb 2024

Publication Type: Journal

Generation of iPSCs from a Patient with the M694V Mutation in the MEFV Gene Associated with Familial Mediterranean Fever and Their Differentiation into Macrophages.

Abstract (Expand)

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder caused by inherited mutations in the MEFV (Mediterranean FeVer) gene, located on chromosome 16 (16p13.3) and encoding the pyrin … protein. Despite the existing data on MEFV mutations, the exact mechanism of their effect on the development of the pathological processes leading to the spontaneous and recurrent autoinflammatory attacks observed in FMF, remains unclear. Induced pluripotent stem cells (iPSCs) are considered an important tool to study the molecular genetic mechanisms of various diseases due to their ability to differentiate into any cell type, including macrophages, which contribute to the development of FMF. In this study, we developed iPSCs from an Armenian patient with FMF carrying the M694V, p.(Met694Val) (c.2080A>G, rs61752717) pathogenic mutation in exon 10 of the MEFV gene. As a result of direct differentiation, macrophages expressing CD14 and CD45 surface markers were obtained. We found that the morphology of macrophages derived from iPSCs of a patient with the MEFV mutation significantly differed from that of macrophages derived from iPSCs of a healthy donor carrying the wild-type MEFV gene. Keywords: Familial Mediterranean fever; MEFV gene; differentiation; macrophages; patient-specific induced pluripotent stem cells.

Authors: Elena V Grigor'eva, Lana V Karapetyan, Anastasia A Malakhova, Sergey P Medvedev, Julia M Minina, Varduhi H Hayrapetyan, Valentina S Vardanyan, Suren M Zakian, Arsen Arakelyan, Roksana Zakharyan

Date Published: 2024

Publication Type: Journal

Development of an optimized, non‐stem cell line for intranasal delivery of therapeutic cargo to the central nervous system

Abstract (Expand)

Neural stem cells (NSCs) are considered to be valuable candidates for delivering a variety of anti-cancer agents, including oncolytic viruses, to brain tumors. However, owing to the previously reported … tumorigenic potential of NSC cell lines after intranasal administration (INA), here we identified the human hepatic stellate cell line LX-2 as a cell type capable of longer resistance to replication of oncolytic adenoviruses (OAVs) as a therapeutic cargo, and that is non-tumorigenic after INA. Our data show that LX-2 cells can longer withstand the OAV XVir-N-31 replication and oncolysis than NSCs. By selecting the highly migratory cell population out of LX-2, an offspring cell line with a higher and more stable capability to migrate was generated. Additionally, as a safety backup, we applied genomic herpes simplex virus thymidine kinase (HSV-TK) integration into LX-2, leading to high vulnerability to ganciclovir (GCV). Histopathological analyses confirmed the absence of neoplasia in the respiratory tracts and brains of immuno-compromised mice 3 months after INA of LX-2 cells. Our data suggest that LX-2 is a novel, robust, and safe cell line for delivering anti-cancer and other therapeutic agents to the brain.

Authors: Ali El‐Ayoubi, Arsen Arakelyan, Moritz Klawitter, Luisa Merk, Siras Hakobyan, Irene Gonzalez‐Menendez, Leticia Quintanilla Fend, Per Sonne Holm, Wolfgang Mikulits, Matthias Schwab, Lusine Danielyan, Ulrike Naumann

Date Published: 26th Dec 2023

Publication Type: Journal

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