Biology subjects

Nissen, I.

Publications and source records attributed to Nissen, I..

6 recordsLinked to original sources

bioRxiv2026

Several multiple sequence alignment perturbation methods enhance AlphaFold3 sampling of alternative protein states

Protein function often involves multiple conformational states. Several multiple sequence alignment-perturbing strategies, including stochastic subsampling, clustering, and column masking, have been shown to enhance AlphaFold2 (AF2) sampling of alternative protein states. Here, we evaluate these strategies on AlphaFold3 (AF3) and compare their performance with the BioEmu Boltzmann sampling model on 107 proteins with multiple experimentally solved conformational states. We find that unperturbed AF3 samples alternative states with significantly higher TM-scores compared to AF2 and comparable to BioEmu. In particular, all MSA perturbation methods improve AF3 sampling at a statistically significant level, improving the top 1% TM-score by at least 0.05 in approximately 20% of cases each, while rarely worsening the performance. Furthermore, we find that different choices of amino acid masks can improve column-masked AF3 sampling for specific targets. Our results highlight how MSA perturbations remain relevant in AF3, providing a useful tool for understanding dynamic biological processes.

biophysics↗

bioRxiv2025

Gene regulatory networks linked to GABA signalling emerge as relevant for glioblastoma pathogenesis

Glioblastoma (GB) is the most common and aggressive adult brain tumor. Recent evidence shows that GB cells form glutamatergic synapses with neurons, promoting tumor growth and invasion, yet the gene regulatory networks (GRNs) underlying this interaction remain underexplored. GRNs coordinate gene expression through interactions among transcription factors (TFs), enhancers, and promoters, and are often disrupted in cancer due to epigenetic and chromatin architecture changes. To identify GRNs involved in GB pathogenesis, we applied the machine learning-based MOBILE (Multi-Omics Binary Integration via Lasso Ensembles) pipeline to integrate multi-omics data. GABA-signalling emerged as a previously unrecognized contributor to GB, involving relevant TFs as ARX, GSX2 and DLX family, key regulators of GABAergic interneuron development. Co-culture assays further demonstrated that GABAergic input promotes GB proliferation through non-synaptic mechanisms likely involving metabolic or paracrine interactions. Our findings reveal novel GRNs in GB, positioning GABA signalling as a potential therapeutic target to disrupt neuron-glioma interactions. SignificanceThis study uncovers novel gene regulatory networks driving glioblastoma progression through integration of multi-omics data with machine-learning tools. By identifying GABAergic signalling as a previously unrecognized contributor to tumour growth, it reveals new transcriptional regulators, providing valuable insights into neuron-glioma interactions. These findings open new therapeutic avenues for brain-cancer treatment. GRAPHICAL ABSTRAC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/651564v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@ed95e1org.highwire.dtl.DTLVardef@b1d9forg.highwire.dtl.DTLVardef@1c5bc00org.highwire.dtl.DTLVardef@b9d833_HPS_FORMAT_FIGEXP M_FIG C_FIG Integration of multi-omics data from glioblastoma (GB) patients identified networks related to GABA signalling as relevant for GB pathogenesis. In co-culture assays, GABAergic interneurons increase the proliferation of GB cells.

genomics↗

bioRxiv2023

fhl2b expression ameliorates muscular dystrophy

In muscular dystrophies, muscle fibers loose integrity and die, leading to significant suffering and a shorter life. Strikingly, the extraocular muscles (EOMs), controlling eye movements, are spared and function well despite the disease progression. Although EOMs have been shown to have important differences compared to body musculature the mechanisms underlying this inherent resistance to muscle dystrophies remain largely unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscle in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is upregulated in response to knockout of desmin, plectin and obscurin, intermediate filament proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival rate. Therefore, fhl2 is a protective agent and a candidate target gene for therapy of muscle dystrophies.

cell biology↗

bioRxiv2023

Epigenomic perturbation of novel EGFR enhancers reduces the proliferative and invasive capacity of glioblastoma and increases sensitivity to temozolomide

Glioblastoma (GB) is the most aggressive of all primary brain tumours. Patients typically rely on radiotherapy with concurrent temozolomide (TMZ) treatment and face a median survival of [~]14 months. Alterations in the Epidermal Growth Factor Receptor gene (EGFR) are common in GB tumours, but therapies targeting EGFR have not shown significant clinical efficacy. Here, we investigated the influence of the EGFR regulatory genome on GB cells, and identified novel EGFR enhancers located in an intronic region nearby the GB-associated SNP rs723527. Epigenomic perturbation of this regulatory region using CRISPR-based methods decreases EGFR expression and reduces the proliferative and invasive capacity of glioblastoma cells, while increasing their sensitivity to TMZ. The enhancer-perturbed GB cells also undergo a metabolic reprogramming in favour of mitochondrial respiration and present increased apoptosis. Our findings demonstrate how epigenomic perturbation of EGFR enhancers can ameliorate the aggressiveness of glioblastoma cells and enhance the efficacy of TMZ treatment. SIGNIFICANCEOur study demonstrates how CRISPR/Cas9-based perturbation of enhancers can be used to modulate the expression of key cancer genes, which can help improve the effectiveness of existing cancer treatments and potentially the prognosis of difficult-to-treat cancers such as glioblastoma.

cancer biology↗

bioRxiv2022

Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication

Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and 3D-chromatin organization result in gene expression changes contributing to cancer pathogenesis. Here, we mapped the promoter-enhancer interactome and regulatory landscape of glioblastoma, the most aggressive primary brain tumour. Our data reveals profound rewiring of promoter-enhancer interactions, chromatin accessibility and redistribution of histone marks across the four glioblastoma subtypes. This leads to loss of long-range regulatory interactions and overall activation of promoters, which orchestrate changes in the expression of genes associated to glutamatergic synapses, axon guidance, axonogenesis and chromatin remodeling. SMAD3 and PITX1 emerge as the major transcription factors controlling genes related to synapse organization and axon guidance. Inhibition of SMAD3 and neuronal activity stimulation cooperate to promote cell proliferation of glioblastoma cells in co-culture with glutamatergic neurons. Our findings provide mechanistic insight into the regulatory networks that mediate neurogliomal synaptic communication.

genomics↗

bioRxiv2020

Within-patient genetic diversity of SARS-CoV-2

SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, is evolving into different genetic variants by accumulating mutations as it spreads globally. In addition to this diversity of consensus genomes across patients, RNA viruses can also display genetic diversity within individual hosts, and co-existing viral variants may affect disease progression and the success of medical interventions. To systematically examine the intra-patient genetic diversity of SARS-CoV-2, we processed a large cohort of 3939 publicly-available deeply sequenced genomes with specialised bioinformatics software, along with 749 recently sequenced samples from Switzerland. We found that the distribution of diversity across patients and across genomic loci is very unbalanced with a minority of hosts and positions accounting for much of the diversity. For example, the D614G variant in the Spike gene, which is present in the consensus sequences of 67.4% of patients, is also highly diverse within hosts, with 29.7% of the public cohort being affected by this coexistence and exhibiting different variants. We also investigated the impact of several technical and epidemiological parameters on genetic heterogeneity and found that age, which is known to be correlated with poor disease outcomes, is a significant predictor of viral genetic diversity. Author SummarySince it arose in late 2019, the new coronavirus (SARS-CoV-2) behind the COVID-19 pandemic has mutated and evolved during its global spread. Individual patients may host different versions, or variants, of the virus, hallmarked by different mutations. We examine the diversity of genetic variants coexisting within patients across a cohort of 3939 publicly accessible samples and 749 recently sequenced samples from Switzerland. We find that a small number of patients carry most of the diversity, and that patients with more diversity tend to be older. We also find that most of the diversity is concentrated in certain regions and positions of the virus genome. In particular, we find that a variant reported to increase infectivity is among the most diverse positions. Our study provides a large-scale survey of within-patient diversity of the SARS-CoV-2 genome.

genomics↗