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93 Publications visible to you, out of a total of 93
The Evolving Faces of the SARS-CoV-2 Genome

Abstract (Expand)

Surveillance of the evolving SARS-CoV-2 genome combined with epidemiological monitoring and emerging vaccination became paramount tasks to control the pandemic which is rapidly changing in time and … space. Genomic surveillance must combine generation and sharing sequence data with appropriate bioinformatics monitoring and analysis methods. We applied molecular portrayal using self-organizing maps machine learning (SOM portrayal) to characterize the diversity of the virus genomes, their mutual relatedness and development since the beginning of the pandemic. The genetic landscape obtained visualizes the relevant mutations in a lineage-specific fashion and provides developmental paths in genetic state space from early lineages towards the variants of concern alpha, beta, gamma and delta. The different genes of the virus have specific footprints in the landscape reflecting their biological impact. SOM portrayal provides a novel option for ‘bioinformatics surveillance’ of the pandemic, with strong odds regarding visualization, intuitive perception and ‘personalization’ of the mutational patterns of the virus genomes.

Authors: Maria Schmidt, Mamoona Arshad, Stephan H. Bernhart, Siras Hakobyan, Arsen Arakelyan, Henry Loeffler-Wirth, Hans Binder

Date Published: 3rd Sep 2021

Publication Type: Journal

A Transcriptome-Wide Isoform Landscape of Melanocytic Nevi and Primary Melanomas Identifies Gene Isoforms Associated with Malignancy.

Abstract (Expand)

Genetic splice variants have become of central interest in recent years, as they play an important role in different cancers. Little is known about splice variants in melanoma. Here, we analyzed a … genome-wide transcriptomic dataset of benign melanocytic nevi and primary melanomas (<i>n</i> = 80) for the expression of specific splice variants. Using kallisto, a map for differentially expressed splice variants in melanoma vs. benign melanocytic nevi was generated. Among the top genes with differentially expressed splice variants were Ras-related in brain 6B (<i>RAB6B</i>), a member of the RAS family of GTPases, Macrophage Scavenger Receptor 1 (<i>MSR1</i>), Collagen Type XI Alpha 2 Chain (<i>COLL11A2</i>), and LY6/PLAUR Domain Containing 1 (<i>LYPD1</i>). The Gene Ontology terms of differentially expressed splice variants showed no enrichment for functional gene sets of melanoma vs. nevus lesions, but between type 1 (pigmentation type) and type 2 (immune response type) melanocytic lesions. A number of genes such as Checkpoint Kinase 1 (<i>CHEK1</i>) showed an association of mutational patterns and occurrence of splice variants in melanoma. Moreover, mutations in genes of the splicing machinery were common in both benign nevi and melanomas, suggesting a common mechanism starting early in melanoma development. Mutations in some of these genes of the splicing machinery, such as Serine and Arginine Rich Splicing Factor A3 and B3 (<i>SF3A3</i>, <i>SF3B3</i>), were significantly enriched in melanomas as compared to benign nevi. Taken together, a map of splice variants in melanoma is presented that shows a multitude of differentially expressed splice genes between benign nevi and primary melanomas. The underlying mechanisms may involve mutations in genes of the splicing machinery.

Authors: Siras Hakobyan, Henry Loeffler-Wirth, Arsen Arakelyan, Hans Binder, Manfred Kunz

Date Published: 2nd Jul 2021

Publication Type: Journal

High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas

Abstract (Expand)

Molecular mechanisms of lower-grade (II–III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendroglioma-like … (IDH-O) tumors both carrying mutations(s) at the isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma resemblance. We generated detailed maps of the transcriptomes and DNA methylomes, revealing that cell functions divided into three major archetypic hallmarks: (i) increased proliferation in IDH-wt and, to a lesser degree, IDH-O; (ii) increased inflammation in IDH-A and IDH-wt; and (iii) the loss of synaptic transmission in all subtypes. Immunogenic properties of IDH-A are diverse, partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We analyzed details of coregulation between gene expression and DNA methylation and of the immunogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby, molecular cartography provides a graphical coordinate system that links gene-level information with glioma subtypes, their phenotypes, and clinical context.

Authors: Edith Willscher, Lydia Hopp, Markus Kreuz, Maria Schmidt, Siras Hakobyan, Arsen Arakelyan, Bettina Hentschel, David T. W. Jones, Stefan M. Pfister, Markus Loeffler, Henry Loeffler-Wirth, Hans Binder

Date Published: 26th Jun 2021

Publication Type: Journal

The radioenhancement potential of Schiff base derived copper (II) compounds against lung carcinoma in vitro.

Abstract (Expand)

For the last years, copper complexes have been intensively implicated in biomedical research as components of cancer treatment. Herewith, we provide highlights of the synthesis, physical measurements, … structural characterization of the newly developed Cu(II) chelates of Schiff Bases, Cu(Picolinyl-L-Tryptopahanate)2, Cu(Picolinyl-L-Tyrosinate)2, Cu(Isonicotinyl-L-Tyrosinate)2, Cu(Picolinyl-L-Phenylalaninate)2, Cu(Nicotinyl-L-Phenylalaninate)2, Cu(Isonicotinyl-L-Phenylalaninate)2, and their radioenhancement capacity at kV and MV ranges of irradiation of human lung carcinoma epithelial cells in vitro. The methods of cell growth, viability and proliferation were used. All compounds exerted very potent radioenhancer capacities in the irradiated lung carcinoma cells at both kV and MV ranges in a 100 μM concentration. At a concentration of 10 μM, only Cu(Picolinyl-L-Tyrosinate)2, Cu(Isonicotinyl-L-Tyrosinate)2, Cu(Picolinyl-L-Phenylalaninate)2 possessed radioenhancer properties at kV and MV ranges. Cu(Picolinyl-L-Tryptophanate)2 showed radioenhancer properties only at kV range. Cu(Nicotinyl-L-Phenylalaninate)2 and Cu(Isonicotinyl-L-Phenylalaninate)2 showed remarkable radioenhancer activity only at MV range. All compounds acted in dose-dependent manner at both tested energy ranges. These copper (II) compounds, in combination with 1 Gy irradiation at either 120 kV or 6 MV, are more efficient at delaying cell growth of lung cancer cells and at reducing cell viability in vitro than the irradiation administered alone. Thus, we have demonstrated that the studied copper compounds have a good potential for radioenhancement.

Authors: Gohar Tsakanova, Ani Stepanyan, Elina Arakelova, Violetta Ayvazyan, Vahan Tonoyan, Arsen Arakelyan, Guido Hildebrandt, Elisabeth Schültke

Date Published: 18th Jun 2021

Publication Type: Journal

Telomere Maintenance Pathway Activity Analysis Enables Tissue- and Gene-Level Inferences.

Abstract (Expand)

Telomere maintenance is one of the mechanisms ensuring indefinite divisions of cancer and stem cells. Good understanding of telomere maintenance mechanisms (TMM) is important for studying cancers and … designing therapies. However, molecular factors triggering selective activation of either the telomerase dependent (TEL) or the alternative lengthening of telomeres (ALT) pathway are poorly understood. In addition, more accurate and easy-to-use methodologies are required for TMM phenotyping. In this study, we have performed literature based reconstruction of signaling pathways for the ALT and TEL TMMs. Gene expression data were used for computational assessment of TMM pathway activities and compared with experimental assays for TEL and ALT. Explicit consideration of pathway topology makes bioinformatics analysis more informative compared to computational methods based on simple summary measures of gene expression. Application to healthy human tissues showed high ALT and TEL pathway activities in testis, and identified genes and pathways that may trigger TMM activation. Our approach offers a novel option for systematic investigation of TMM activation patterns across cancers and healthy tissues for dissecting pathway-based molecular markers with diagnostic impact.

Authors: L. Nersisyan, A. Simonyan, H. Binder, A. Arakelyan

Date Published: 26th Apr 2021

Publication Type: Journal

Long-Term Effects of Very Low Dose Particle Radiation on Gene Expression in the Heart: Degenerative Disease Risks

Abstract (Expand)

Compared to low doses of gamma irradiation (γ-IR), high-charge-and-energy (HZE) particle IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be … IR type and dose dependent. Three- to four-month-old female CB6F1/Hsd mice were exposed once to one of four different doses of the following types of radiation: γ-IR 137Cs (40-160 cGy, 0.662 MeV), 14Si-IR (4-32 cGy, 260 MeV/n), or 22Ti-IR (3-26 cGy, 1 GeV/n). At 16 months post-exposure, animals were sacrificed and hearts were harvested and archived as part of the NASA Space Radiation Tissue Sharing Forum. These heart tissue samples were used in our study for RNA isolation and microarray hybridization. Functional annotation of twofold up/down differentially expressed genes (DEGs) and bioinformatics analyses revealed the following: (i) there were no clear lower IR thresholds for HZE- or γ-IR; (ii) there were 12 common DEGs across all 3 IR types; (iii) these 12 overlapping genes predicted various degrees of cardiovascular, pulmonary, and metabolic diseases, cancer, and aging; and (iv) these 12 genes revealed an exclusive non-linear DEG pattern in 14Si- and 22Ti-IR-exposed hearts, whereas two-thirds of γ-IR-exposed hearts revealed a linear pattern of DEGs. Thus, our study may provide experimental evidence of excess relative risk (ERR) quantification of low/very low doses of full-body space-type IR-associated degenerative disease development.

Authors: Venkata Naga Srikanth Garikipati, Arsen Arakelyan, Eleanor A. Blakely, Polly Y. Chang, May M. Truongcao, Maria Cimini, Vandana Malaredy, Anamika Bajpai, Sankar Addya, Malik Bisserier, Agnieszka Brojakowska, Abrisham Eskandari, Mary K. Khlgatian, Lahouaria Hadri, Kenneth M. Fish, Raj Kishore, David. A. Goukassian

Date Published: 13th Feb 2021

Publication Type: Journal

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Abstract (Expand)

Mutations in the BRCA1 and BRCA2 genes are known risk factors and drivers of breast and ovarian cancers. So far, few studies have been focused on understanding the differences in transcriptome and …d functional landscapes associated with the disease (breast vs. ovarian cancers), gene (BRCA1 vs. BRCA2), and mutation type (germline vs. somatic). In this study, we were aimed at systemic evaluation of the association of BRCA1 and BRCA2 germline and somatic mutations with gene expression, disease clinical features, outcome, and treatment. We performed BRCA1/2 mutation centered RNA-seq data analysis of breast and ovarian cancers from the TCGA repository using transcriptome and phenotype “portrayal” with multi-layer self-organizing maps and functional annotation. The results revealed considerable differences in BRCA1- and BRCA2-dependent transcriptome landscapes in the studied cancers. Furthermore, our data indicated that somatic and germline mutations for both genes are characterized by deregulation of different biological functions and differential associations with phenotype characteristics and poly(ADP-ribose) polymerase (PARP)-inhibitor gene signatures. Overall, this study demonstrates considerable variation in transcriptomic landscapes of breast and ovarian cancers associated with the affected gene (BRCA1 vs. BRCA2), as well as the mutation type (somatic vs. germline). These results warrant further investigations with larger groups of mutation carriers aimed at refining the understanding of molecular mechanisms of breast and ovarian cancers.

Authors: Arsen Arakelyan, Ani Melkonyan, Siras Hakobyan, Uljana Boyarskih, Arman Simonyan, Lilit Nersisyan, Maria Nikoghosyan, Maxim Filipenko, Hans Binder

Date Published: 28th Jan 2021

Publication Type: Journal

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