Biology subjects

Hornblad, A.

Publications and source records attributed to Hornblad, A..

4 recordsLinked to original sources

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

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

Dissection of the Fgf8 regulatory landscape by in vivo CRISPR-editing reveals extensive inter- and intra-enhancer redundancy

Developmental genes are often regulated by multiple elements with overlapping activity. Yet, in most cases, the relative function of those elements and their contribution to endogenous gene expression remain uncharacterized. Illustrating this situation, distinct sets of enhancers have been proposed to direct Fgf8 in the limb apical ectodermal ridge (AER) and the midbrain-hindbrain boundary (MHB). Using in vivo CRISPR/Cas9 genome engineering, we functionally dissect this complex regulatory ensemble and demonstrate two distinct regulatory logics. In the AER, the control of Fgf8 expression appears extremely distributed between different enhancers. In contrast, in the MHB, one of the three active enhancers is essential while the other two are dispensable. Further dissection of the essential MHB enhancer revealed another layer of redundancy and identified two sub-parts required independently for Fgf8 expression and formation of midbrain and cerebellar structures. Interestingly, cross-species transgenic analysis of this enhancer suggests changes of the organisation of this essential regulatory node in the vertebrate lineage.

developmental biology↗