Biology subjects

Varisco, M.

Publications and source records attributed to Varisco, M..

6 recordsLinked to original sources

bioRxiv2026

Atlantis: An integrative database for human proteome structural and functional sites

Understanding protein mechanisms in health and disease requires characterizing the functional roles of individual amino acid residues. To explore the role of residues and their mutations, we have developed Atlantis, a database that integrates structural and functional information at the human proteome residue level. A graph database enables complex queries and the retrieval of integrated information for multiple functional analysis of protein systems. A Model Context Protocol (MCP) connector allows the interrogation of the resource through Large Language Models (LLMs) or agentic frameworks for biomedical research. Atlantis annotates over 11M residues across 20k human proteins, identifying hundreds thousands intra- and inter-protein contacts in PDB as well as AlphaFoldDB structures. We also provide the possibility to analyze and integrate predicted 3D complexes inputted by the user, and we showcased these features on hundreds of AlphaFold-multimer complexes of GPCRs and LRRK2 interaction networks. The tool is freely accessible at https://atlantis.bioinfolab.sns.it/.

bioinformatics↗

bioRxiv2026

The mutational landscape of innervation axes in cancer

The mutational landscape of neural innervation axes in cancer has garnered increasing attention due to their significant influence on tumorigenesis, metastasis, and treatment resistance. This study provides an overview of the alterations of neural signaling pathways based on multi-omics data analysis. In particular, we conducted a comprehensive analysis of mutations in key genes associated with neurotrophin signaling, norepinephrine and cholinergic pathways, alongside paracrine and synaptogenic factors. Our findings reveal that 65% of patients in a pancancer cohort exhibit at least one somatic alteration in these pathways, with neurotrophin genes being the most frequently altered. Notably, alterations in these genes (e.g., NGF) correlate with poor patient survival across various cancer types, suggesting their oncogenic potential. We also identified significant co-occurrence of mutations and differential expression patterns from both bulk and single-cell RNAseq data, indicating complex interactions among these pathways that contribute to tumor innervation and neuroplasticity. This study underscores the necessity of understanding the crosstalk between neural signaling and cancer biology to improve patient stratification based on mutational profiles and identify potential therapeutic targets. Further research utilizing advanced genomic techniques is essential to elucidate the mechanistic roles of these pathways in tumor innervation.

genomics↗

bioRxiv2025

Heterotypic directional motifs contribute to TAD boundary function in Drosophila

While convergent CTCF binding sites are essential for topologically associating domain (TAD) formation in mammals, how TADs are formed in other species remains unclear. In Drosophila, TAD boundaries lack convergent CTCF sites and are occupied by different insulator protein combinations with no obvious pairing rules. To identify sequence features required for boundary pairing, we inserted different endogenous boundaries into two Drosophila TADs in both orientations, creating 53 ectopic insertions and measured their ability to form interactions with the endogenous boundaries to their left and right. 70% of inserted boundaries had context- and/or orientation-dependent effects, indicating specificity and directionality encoded in their sequence. Known insulator motifs or promoters could not explain boundary specificity. Instead, we identified heterotypic pairs of directional motifs that predict compatible boundary pairs. Our results indicate that directional motif pairs are a conserved property of boundaries from flies to mammals, but gained complexity in Drosophila through heterotypic combinations.

genomics↗

bioRxiv2025

Communication breakdown and evolution of the cancer cell

1We studied cell-cell interactions (CCIs) in large-scale transcriptomic datasets, which showed higher co-expression in cancer compared to healthy tissues. CCIs are more co-expressed than any other type of intracellular interaction and, likewise, they are the protein-protein interaction (PPI) class that is most co-evolved in sequenced genomes. Similar trends of stricter regulation and evolutionary pressure are observed when comparing extracellular versus intracellular interactions mediated by G protein Coupled Receptors (GPCRs), whose ligand interactions are also characterized by a higher mutational burden in later tumor stages when considering somatic mutations associated with tumor clonal evolution. CCIs undergo the most extensive rewiring of their tumor co-expression networks relative to healthy tissues, more so than any other PPI type, with a set of CCI hubs highly conserved across multiple tumor tissues, and a higher diversity on healthy ones. Cancer rewiring is also associated with the formation of recurrent circuits of co-expressed CCI pairs, represented by enriched network motifs such as triad or tetrad cliques. These act as integrative hotspots to facilitate the crosstalk of distinct processes and the interaction of the cancer cell with its tumor microenvironment (TME). Remarkably, many CCI circuits are significantly associated with patient survival and are predictive of patient response to immunotherapy. CCI circuits mapping to allograft rejection and inflammatory response inform immunotherapy response prediction, while those related to epithelial-mesenchymal transition are associated with poorer prognosis. Overall, we show that CCIs expression signatures could be effectively exploited to stratify patients and, at the same time, they highlight new combination therapeutic opportunities in personalized medicine settings.

bioinformatics↗

bioRxiv2023

Tau alters global gene expression affecting chromatin in the early stages of Alzheimer's disease

Recent research revealed that Tau plays critical roles in various neuronal functions. Our previous work demonstrated that destabilization and nuclear delocalization of Tau can alter the expression of glutamatergic genes, thereby mediating early neuronal damage. Upon analysing gene coexpression of AD temporal regions at different stages and the transcriptional output in differentiated neuroblastoma cells, we discovered that changes in Tau availability are linked to global alterations in gene expression that affect multiple neuronal pathways. Comparison with the human AD temporal region showed that the Tau-dependent modulation of gene expression closely resembles an intermediate stage of AD that precedes the definitive AD condition. Furthermore, we identified the chromatin remodelling pathway as being significantly affected by Tau in both our cellular model and AD brains, with reductions in heterochromatin markers. We propose that Tau is able to globally affect the neuronal transcriptome and that its availability is linked to changes in gene expression during intermediate stages of AD development. In addition, we found that the epigenetic pathway is strongly affected by Tau during the progression of AD.

neuroscience↗

bioRxiv2018

Nuclear Tau modulates VGluT1 expression: a new function for Tau

Summary\n\nTau displacement from microtubules is the first step in the onset of tauopathies, and is followed by toxic protein aggregation. However, other non-canonical functions of Tau might have a role in these pathologies. Here, we demonstrate that a small amount of Tau localizes in the nuclear compartment and accumulates in both the soluble and DNA-bound fractions. We show that nuclear Tau regulates the expression of VGluT1, a disease-relevant gene directly involved in glutamatergic synaptic transmission. Impeding Tau/tubulin interaction in the cytosol favours its nuclear translocation and increases VGluT1 expression. Remarkably, the P301L mutation impairs this mechanism leading to a loss of function. Altogether, our results provide the demonstration of a direct physiological role of Tau on gene expression. Alterations of this mechanism may be at the basis of the onset of neurodegeneration.

molecular biology↗