Biology subjects

de la Grange, P.

Publications and source records attributed to de la Grange, P..

5 recordsLinked to original sources

bioRxiv2025

HnRNP C binding to inverted Alu elements protects the transcriptome from pre-mRNA circularization

Back-splicing is a non-canonical splicing event that drives the biogenesis of circular RNAs (circRNAs). Although the molecular mechanisms underlying circRNA biogenesis have been partially elucidated, how this process is globally regulated in tumors, has not been fully investigated. Herein, we uncover a hnRNP C-dependent mechanism that represses a broad repertoire of circRNAs in Group 3 medulloblastoma (MB). HnRNP C binds Alu elements and prevents the circularization of pre-mRNA transcripts. Expression of hnRNP C modulates the balance between linear and circular splicing and guarantees efficient expression of genes that sustain the oncogenic phenotype of Group 3 MB cells. Remarkably, in the absence of hnRNP C, the introns flanking the circularizing exons generate cytoplasmic dsRNAs through base-pairing of inverted Alu elements and trigger an interferon-induced antiviral response. These findings unveil the role of hnRNP C as guardian of transcriptome integrity by repressing circRNA biogenesis. Lastly, targeting hnRNP C in Group 3 MB may trigger an inflammatory immune response, thereby boosting cancer surveillance.

cancer biology↗

bioRxiv2025

Regulation of NTRK2 alternative splicing by PRPF40B controls neural differentiation and synaptic plasticity

BDNF signaling through its receptor TRKB plays a critical role in brain development, neuroplasticity and homeostasis. Alternative splicing of the TRKB gene, NTRK2, generates either the full-length receptor (TRKB-FL) or a truncated isoform (TRKB-T1) that inhibits BDNF signaling and has been implicated in neurodegenerative diseases, psychiatric disorders and cognitive impairments. Here, we show that PRPF40B, a splicing factor associated with neuronal dysfunction, promotes production of the TRKB-FL isoform during neuronal differentiation. Silencing PRPF40B increases TRKB-T1 expression, impairing expression of genes important for neuronal differentiation and synaptic plasticity. Our data thus identify PRPF40B as a key regulator of the balance between TRKB receptor isoforms, crucial for fine-tuning neuronal responses and for preventing neuroplasticity or survival impairments, providing also a mechanism for the role of PRPF40B in the pathogenesis of various human neurodegenerative diseases and psychiatric disorders

cell biology↗

bioRxiv2020

Oligodendrocyte secreted factors shape hippocampal GABAergic neuron transcriptome and physiology

Oligodendrocytes form myelin for central nervous system axons and release factors which signal to neurons during myelination. Here, we ask how oligodendroglial factors influence hippocampal GABAergic neuron physiology. In mixed hippocampal cultures GABAergic neurons fired action potentials of short duration and received high frequencies of excitatory synaptic events. In purified neuronal cultures without glial cells, GABAergic neuron excitability increased and the frequency of synaptic events decreased. These effects were largely reversed by adding oligodendrocyte conditioned medium. We compared the transcriptomic signature with the electrophysiological phenotype of single neurons in these three culture conditions. Genes expressed by single pyramidal or GABAergic neurons largely conformed to expected cell-type specific patterns. Multiple genes of GABAergic neurons were significantly downregulated by the transition from mixed cultures containing glial cells to purified neuronal cultures. Levels of these genes were restored by the addition of oligodendrocyte conditioned medium to purified cultures. Clustering genes with similar changes in expression between different culture conditions revealed processes affected by oligodendroglial factors. Enriched genes are linked to roles in synapse assembly, action potential generation and transmembrane ion transport, including of zinc. These results provide new insight into the molecular targets by which oligodendrocytes influence neuron excitability and synaptic function.

neuroscience↗

bioRxiv2020

Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial epithelial progenitors from Chronic Obstructive Pulmonary Disease

Patients with COPD have many anomalies in their airway epithelium, and their basal stem/progenitor cells show a decrease in self-renewal and differentiation potential. The objective of this study was to identify deregulations in the genetic program of COPD bronchial basal stem/progenitor cells that could account for their exhaustion. TGF-{beta} is found at higher levels in the lungs of COPD subjects. It has been shown to play a role in stem/progenitor cell fate and also to regulate the expression of the EMT-inducing transcription factor Slug/Snail2. In contrast to other transcription factors of the Snail family, Slug is highly expressed in basal progenitor cells, the adult stem/progenitors of human airway epithelium. We aimed at identifying genes downstream of Slug that respond to TGF-{beta}, and whose expression is deregulated in COPD airway basal stem/progenitor cells, and could account for the decrease in count and functional ability of these cells observed in COPD. For this, we knocked down Slug in primary bronchial basal progenitor cells from COPD and normal subjects and, among the genes downstream of Slug, we selected those responding to TGF-{beta} and differentiation. We identified 5 genes coding for transcription factors involved in stem cell maintenance that are repressed downstream of Slug and by TGF-{beta} in COPD but not normal basal progenitor cells. Our results bring a molecular perspective to the exhaustion of airway basal stem/progenitor cells observed in COPD by revealing that stem cell maintenance genes are repressed in these cells, with TGF-{beta} and Slug being involved in this deregulation.

genomics↗

bioRxiv2019

Slug/Snail2 is involved in the repression of proliferation genes by TGF-β in bronchial epithelial progenitor cells and is deregulated in abnormal epithelium

Slug/Snail2 belongs to the Epithelial-Mesenchymal Transition (EMT)-inducing transcription factors involved in development and diseases. Slug is expressed in adult stem/progenitor cells of several epithelia, making it unique among these transcription factors. To investigate Slug role in human bronchial epithelium progenitors, we studied primary bronchial basal/progenitor cells in an air-liquid interface culture system that allows regenerating a bronchial epithelium. To identify Slug downstream genes we knocked down Slug in basal/progenitor cells from normal subjects and subjects with COPD, a respiratory disease presenting anomalies in the bronchial epithelium and high levels of TGF-{beta} in the lungs. We show that normal and COPD bronchial basal/progenitors, even when treated with TGF-{beta}, express both epithelial and mesenchymal markers, and that the epithelial marker E-cadherin is not a target of Slug and, moreover, positively correlates with Slug. We reveal that Slug downstream genes responding to both differentiation and TGF-{beta} are different in normal and COPD progenitors, with in particular a set of proliferation-related genes that are among the genes repressed downstream of Slug in normal but not COPD. In COPD progenitors at the onset of differentiation in presence of TGF-{beta}, we show that there is positive correlations between the effect of differentiation and TGF-{beta} on proliferation-related genes and on Slug protein, and that their expression levels are higher than in normal cells. As well, the expression of Smad3 and {beta}-Catenin, two molecules from TGF-{beta} signaling pathways, are higher in COPD progenitors, and our results indicate that proliferation-related genes and Slug protein are increased by different TGF-{beta}-induced mechanisms. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/674127v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@524a15org.highwire.dtl.DTLVardef@7dd1e5org.highwire.dtl.DTLVardef@5f3798org.highwire.dtl.DTLVardef@13ae179_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗