Biology subjects

Hrsak, D.

Publications and source records attributed to Hrsak, D..

3 recordsLinked to original sources

bioRxiv2026

Long-range regulatory target prediction reveals shared genetic background across ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and ankylosing spondylitis

Common variants detected by the genome-wide association studies (GWAS) create a wealth of knowledge on genetic component of individual traits and diseases. Elucidating the molecular mechanism behind the vast majority of these variants that are found to be non-coding remains a largely unsolved task, especially when distal and pleiotropic interactions between regulatory elements where these variants occur and gene promoters are taken into account. Focusing on four diseases with immune-mediated mechanisms namely ulcerative colitis, Crohns disease, primary sclerosing cholangitis and ankylosing spondylitis, we demonstrate the utility of the targPred tool, providing prediction of genes targeted by the regulatory variants. We demonstrate that taking into account evolutionary and comparative genomic data, previously unobserved mechanistic trends (the platelet, vascular and sterol clusters) can be detected in terms of implicated genes targeted by the regulatory elements containing common variants, shared between all four diseases, as well as specific trends for subsets of diseases, e.g. two IBD phenotypes. We also elucidate a clinically-relevant target COG6 shared between IBD and PSC, as well as a whole range of other target genes missed by the conventional SNP-to-gene assignments methods.

genomics↗

bioRxiv2026

The role of long-range transcriptional regulation in interpretation of non-coding variants associated with human disease

Genome-wide association studies (GWAS) are the key tools for the discovery of associations between single nucleotide polymorphisms (SNPs) and phenotypic traits and have been successfully applied to many diseases and disorders. However, a great challenge is to find the gene affected by the non-coding fraction of SNPs, especially if the gene is distal in terms of genomic distance. In this study, we present a novel approach, named targPred, which utilises genomic regulatory blocks (GRBs) for inference of a connection between a certain SNP/locus and the target gene located in the same GRB, in a more robust and generalisable manner. We identified that many disease traits such as cancer and psychiatric disease have a propensity for long-range regulation. Furthermore, we showcased a childhood obesity locus which is connected to the distal BDNF gene. Finally, we propose a new web-based service based on enhancer-promoter association, to facilitate finding the causal genes for a wide array of traits and conditions.

genomics↗

bioRxiv2025

Regulation of reticular adhesions by KANK2 and talin2 in two melanoma cell lines

Integrins bind to extracellular matrix proteins and, upon clustering, form multimolecular integrin adhesion complexes (IACs) that connect to and regulate the cell cytoskeleton, influencing various aspects of normal and tumour cell behaviour. Alongside well-characterized nascent adhesions, focal adhesions (FAs), fibrillar adhesions (FBs) and hemidesmosomes, a new class of IACs, reticular adhesions (RAs), have been identified. RAs, initially described as flat clathrin lattices formed by integrin V{beta}5, lack association with actin and are devoid of FAs markers. The physiological role of RAs in normal and tumor cells is still incompletely understood and requires further investigation. Previously, we analysed IACs of two melanoma cell lines, MDA-MB-435S and RPMI-7951, grown under long term culture conditions, and demonstrated that both cell lines preferentially use integrin V{beta}5 for adhesion. Here we present a comprehensive analysis of RAs in these two melanoma cell lines that differ in their ability to form FBs. To determine RAs composition, we treated cells with actin polymerisation inhibitor cytochalasin D (CytoD) which disrupts FAs, allowing isolation of RAs, which were analysed by MS-based proteomics, Western blotting and immunofluorescence. Known RA-associated proteins, including the AP-2 adaptor complex, disabled homolog 2 (DAB2) and Numb were identified in both lines, along with talin2. Notably, we also detected the presence of KN motif and ankyrin repeat domains protein (KANK2) in RA isolates. Proximity ligation analysis following CytoD-induced actin disruption confirmed the proximity of KANK2 and talin2 in RAs. We then investigated the effect of talin2 or KANK2 knockdown on RAs composition. While both talin2 and KANK2 are located in RAs, neither is essential for RA formation. Talin2 knockdown led to a reduction in RA components abundance in both cell lines. In MDA-MB-435S cell line, KANK2 produced a similar effect, mirroring the functional interaction of talin2 and KANK2 in FAs. However, in RPMI-7951 cells, KANK2 knockdown had no significant effect on RA components abundance. This discrepancy likely reflects the preferential localization of KANK2 in FBs and underscores the differing roles of talin2 and KANK2 in V{beta}5-mediated FAs across the two cell lines. These findings underscore the complexity of adhesion signalling and highlight the importance of adhesion crosstalk in regulating cellular function.

cell biology↗