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41 Publications visible to you, out of a total of 41
Transcriptome alterations in long-term mining region residents: Insights into immune response and molecular pathways.

Abstract (Expand)

Pollution with metals and metalloids is a global problem that adversely affects human health and environment. Although several studies have reported gene expression changes in response to human exposures … to metals, there are a limited number of studies exploring the effect of long-term residence in mining areas. The evidence of increased levels of several essential and non-essential metals in soil, water, and plants in Kapan mining area (Armenia) has been previously demonstrated in several environmental studies. Our study investigated the impact of long-term residence in this mining area on the transcriptome state of human peripheral blood mononuclear cells and the possible association of transcriptome changes with the blood metallome. In total, 58 participants including 27 mining region residents (MRR) and 31 non-mining region residents (NMR) were selected for our study. Transcriptomic analysis of peripheral blood mononuclear cells was performed by mRNA sequencing. Differential expression analyses were conducted using generalized linear modeling, optimized for participant demographics, cell types, and sequencing technical factors, followed by pathway analysis. The study revealed that long-term residence in a mining area is correlated with alterations in the blood transcriptome, with responses varying by sex. The identified transcriptome changes were enriched for pathways related to immune response and RNA translation. These changes correlated with higher blood levels of a mixture of non-essential metals, including arsenic, antimony, nickel, thallium, and beryllium. Additionally, the study identified differences in the transcriptome response between male and female MRR. While females exhibited a stronger immune response, males show dysregulation in ion transport and epigenetic modifications. Our findings contribute to understanding the effects of long-term residence in mining regions and can aid in developing more effective risk assessment and mitigation approaches in target populations.

Authors: A. Stepanyan, A. Arakelyan, J. Schug

Date Published: 24th Mar 2025

Publication Type: Journal

Molecular Epidemiology and In-Depth Characterization of Klebsiella pneumoniae Clinical Isolates from Armenia

Abstract (Expand)

The global dissemination of Klebsiella pneumoniae pathotypes with multidrug-resistant (MDR) and hypervirulent traits poses a threat to public health. The situation in Armenia is unclear, and we performed … a comprehensive characterisation of 48 clinical isolates of K. pneumoniae, collected from 2018 to 2024. The majority of the isolates (64.58%) were extensively drug-resistant (XDR) and MDR. Genomic analysis of 21 isolates revealed the presence of international high-risk MDR clones (ST395, ST15, and ST307). The ST395 strains were isolated from children and resisted the first-line drugs such as beta-lactams. These isolates harboured a range of virulence determinants, from capsule polysaccharides to siderophores to regulators of the mucoid phenotype. The ST395 strains are enriched by ICEs, plasmids, and prophages, on which antimicrobial resistance (AMR) and virulence genes are located and which may lead to the convergence of MDR and hypervirulent traits. There is a widespread non-specific AMR mechanism among our K. pneumoniae strains. These are mutations in the porin genes, which reduce permeability to antimicrobials, and mutations in the regulators of efflux pumps, which lead to overexpression of drug efflux pumps such as AcrAB. These mechanisms may contribute to the elevated MICs and confer AMR to strains with no specific AMR genes.

Authors: Anahit Sedrakyan, Zaruhi Gevorgyan, Magdalina Zakharyan, Karine Arakelova, Shoghik Hakobyan, Alvard Hovhannisyan, Rustam Aminov

Date Published: 9th Jan 2025

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

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

Long-term environmental metal exposure is associated with hypomethylation of CpG sites in NFKB1 and other genes related to oncogenesis.

Abstract (Expand)

BACKGROUND: Long-term environmental exposure to metals leads to epigenetic changes and may increase risks to human health. The relationship between the type and level of metal exposure and epigenetic … changes in subjects exposed to high concentrations of metals in the environment is not yet clear. The aim of our study is to find the possible association of environmental long-term exposure to metals with DNA methylation changes of genes related to immune response and carcinogenesis. We investigated the association of plasma levels of 21 essential and non-essential metals detected by ICP-MS and the methylation level of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5, IGF2 and H19 genes assessed by targeted bisulfite sequencing in a cohort of 40 subjects living near metal mining area and 40 unexposed subjects. Linear regression was conducted to find differentially methylated positions with adjustment for gender, age, BMI class, smoking and metal concentration. RESULTS: In the metal-exposed group, five CpGs in the NFKB1 promoter region were hypomethylated compared to unexposed group. Four differentially methylated positions (DMPs) were associated with multiple metals, two of them are located on NFKB1 gene, and one each on CDKN2A gene and ESR1 gene. Two DMPs located on NFKB1 (chr4:102500951, associated with Be) and IGF2 (chr11:2134198, associated with U) are associated with specific metal levels. The methylation status of the seven CpGs located on NFKB1 (3), ESR1 (2) and CDKN2A (2) positively correlated with plasma levels of seven metals (As, Sb, Zn, Ni, U, I and Mn). CONCLUSIONS: Our study revealed methylation changes in NFKB1, CDKN2A, IGF2 and ESR1 genes in individuals with long-term human exposure to metals. Further studies are needed to clarify the effect of environmental metal exposure on epigenetic mechanisms and pathways involved.

Authors: A. Stepanyan, A. Petrackova, S. Hakobyan, J. Savara, S. Davitavyan, E. Kriegova, A. Arakelyan

Date Published: 7th Aug 2023

Publication Type: Journal

Atlas of mRNA translation and decay for bacteria.

Abstract (Expand)

Regulation of messenger RNA stability is pivotal for programmed gene expression in bacteria and is achieved by a myriad of molecular mechanisms. By bulk sequencing of 5' monophosphorylated mRNA … decay intermediates (5'P), we show that cotranslational mRNA degradation is conserved among both Gram-positive and -negative bacteria. We demonstrate that, in species with 5'-3' exonucleases, the exoribonuclease RNase J tracks the trailing ribosome to produce an in vivo single-nucleotide toeprint of the 5' position of the ribosome. In other species lacking 5'-3' exonucleases, ribosome positioning alters endonucleolytic cleavage sites. Using our metadegradome (5'P degradome) sequencing approach, we characterize 5'P mRNA decay intermediates in 96 species including Bacillus subtilis, Escherichia coli, Synechocystis spp. and Prevotella copri and identify codon- and gene-level ribosome stalling responses to stress and drug treatment. We also apply 5'P sequencing to complex clinical and environmental microbiomes and demonstrate that metadegradome sequencing provides fast, species-specific posttranscriptional characterization of responses to drug or environmental perturbations. Finally we produce a degradome atlas for 96 species to enable analysis of mechanisms of RNA degradation in bacteria. Our work paves the way for the application of metadegradome sequencing to investigation of posttranscriptional regulation in unculturable species and complex microbial communities.

Authors: S. Huch, L. Nersisyan, M. Ropat, D. Barrett, M. Wu, J. Wang, V. D. Valeriano, N. Vardazaryan, J. Huerta-Cepas, W. Wei, J. Du, L. M. Steinmetz, L. Engstrand, V. Pelechano

Date Published: 5th Jun 2023

Publication Type: Journal

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