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12 Publications visible to you, out of a total of 12
Topology-aware pathway analysis of spatial transcriptomics

Abstract (Expand)

Spatial transcriptomics (ST) has transformed genomics by mapping gene expression onto intact tissue architecture, uncovering intricate cellular interactions that bulk and single-cell RNA sequencing … often overlook. Traditional ST workflows typically involve clustering spots, performing differential expression analyses, and annotating results via gene-set methods such as overrepresentation analysis (ORA) or gene set enrichment analysis (GSEA). More recent spatially-aware techniques extend these approaches by incorporating tissue organization into gene-set scoring. However, because they operate primarily at the level of individual genes, they may overlook the connectivity and topology of biological pathways, limiting their capacity to trace the propagation of signaling events within tissue regions. In this study, we address that gap by translating gene expression into pathway-level activity using the Pathway Signal Flow (PSF) algorithm. PSF integrates expression data with curated interaction networks to compute numeric activity scores for each branch of a biological pathway, producing a functionally annotated feature space that captures downstream signaling effects as branch-specific activity values. We applied PSF to two public 10x Genomics Visium datasets (human melanoma and mouse brain) and compared clustering based on PSF-derived pathway activities from 40 curated Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways and gene expression with standard Seurat Louvain clustering and spatially aware methods (Vesalius, spatialGE). We observed good correspondence between PSF-based and expression-based clustering when spatially aware clustering methods were used. This suggests that branch-level pathway activities can themselves drive clustering and pinpoint spatially deregulated processes. To assess cluster-specific functional annotation, we compared PSF results to conventional ORA (based on marker genes) and GSDensity (based on cluster-specific gene sets). PSF identified a broader set of significant pathways with substantial overlap with both ORA and GSDensity, providing increased sensitivity due to its branch-level resolution. We further demonstrated that PSF-derived activity values can be used to detect spatially deregulated pathway branches, yielding results comparable to those obtained with spatially aware gene set analysis approaches such as GSDensity and spatialGE. The availability of pathway topology and branch-specific information also enabled the identification of potential intercellular communication via ligand-receptor interactions between deregulated pathways in adjacent tumor regions. To support interactive exploration of results, we developed the PSF Spatial Browser, an R Shiny application for visualizing pathway activities, gene expression patterns, and deregulated pathway networks.

Authors: Siras Hakobyan, Maria Schmidt, H. Binder, A. Arakelyan

Date Published: 14th Aug 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

PSF toolkit: an R package for pathway curation and topology-aware analysis.

Abstract (Expand)

Most high throughput genomic data analysis pipelines currently rely on over-representation or gene set enrichment analysis (ORA/GSEA) approaches for functional analysis. In contrast, topology-based … pathway analysis methods, which offer a more biologically informed perspective by incorporating interaction and topology information, have remained underutilized and inaccessible due to various limiting factors. These methods heavily rely on the quality of pathway topologies and often utilize predefined topologies from databases without assessing their correctness. To address these issues and make topology-aware pathway analysis more accessible and flexible, we introduce the PSF (Pathway Signal Flow) toolkit R package. Our toolkit integrates pathway curation and topology-based analysis, providing interactive and command-line tools that facilitate pathway importation, correction, and modification from diverse sources. This enables users to perform topology-based pathway signal flow analysis in both interactive and command-line modes. To showcase the toolkit's usability, we curated 36 KEGG signaling pathways and conducted several use-case studies, comparing our method with ORA and the topology-based signaling pathway impact analysis (SPIA) method. The results demonstrate that the algorithm can effectively identify ORA enriched pathways while providing more detailed branch-level information. Moreover, in contrast to the SPIA method, it offers the advantage of being cut-off free and less susceptible to the variability caused by selection thresholds. By combining pathway curation and topology-based analysis, the PSF toolkit enhances the quality, flexibility, and accessibility of topology-aware pathway analysis. Researchers can now easily import pathways from various sources, correct and modify them as needed, and perform detailed topology-based pathway signal flow analysis. In summary, our PSF toolkit offers an integrated solution that addresses the limitations of current topology-based pathway analysis methods. By providing interactive and command-line tools for pathway curation and topology-based analysis, we empower researchers to conduct comprehensive pathway analyses across a wide range of applications.

Authors: S. Hakobyan, A. Stepanyan, L. Nersisyan, H. Binder, A. Arakelyan

Date Published: 8th Sep 2023

Publication Type: Journal

Projection of High-Dimensional Genome-Wide Expression on SOM Transcriptome Landscapes

Abstract (Expand)

organizing maps portraying has been proven to be a powerful approach for analysis of transcriptomic, genomic, epigenetic, single-cell, and pathway-level data as well as for “multi-omic” integrative … analyses. However, the SOM method has a major disadvantage: it requires the retraining of the entire dataset once a new sample is added, which can be resource- and time-demanding. It also shifts the gene landscape, thus complicating the interpretation and comparison of results. To overcome this issue, we have developed two approaches of transfer learning that allow for extending SOM space with new samples, meanwhile preserving its intrinsic structure. The extension SOM (exSOM) approach is based on adding secondary data to the existing SOM space by “meta-gene adaptation”, while supervised SOM portrayal (supSOM) adds support vector machine regression model on top of the original SOM algorithm to “predict” the portrait of a new sample. Both methods have been shown to accurately combine existing and new data. With simulated data, exSOM outperforms supSOM for accuracy, while supSOM significantly reduces the computing time and outperforms exSOM for this parameter. Analysis of real datasets demonstrated the validity of the projection methods with independent datasets mapped on existing SOM space. Moreover, both methods well handle the projection of samples with new characteristics that were not present in training datasets.

Authors: Maria Nikoghosyan, Henry Loeffler-Wirth, Suren Davidavyan, Hans Binder, Arsen Arakelyan

Date Published: 27th Dec 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

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

oposSOM-Browser: an interactive tool to explore omics data landscapes in health science.

Abstract (Expand)

Background: oposSOM is a comprehensive, machine learning based open-source data analysis software combining functionalities such as diversity analyses, biomarker selection, function mining, and … visualization. Results: These functionalities are now available as interactive web-browser application for a broader user audience interested in extracting detailed information from high-throughput omics data sets pre-processed by oposSOM. It enables interactive browsing of single-gene and gene set profiles, of molecular 'portrait landscapes', of associated phenotype diversity, and signalling pathway activation patterns. Conclusion: The oposSOM-Browser makes available interactive data browsing for five transcriptome data sets of cancer (melanomas, B-cell lymphomas, gliomas) and of peripheral blood (sepsis and healthy individuals) at www.izbi.uni-leipzig.de/opossom-browser . Keywords: Interactive data analysis; Results browser; Transcriptomics.

Authors: Henry Loeffler-Wirth, Jasmin Reikowski, Siras Hakobyan, Jonas Wagner, Hans Binder

Date Published: 19th Oct 2020

Publication Type: Journal

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