Biology subjects

Mortreux, F.

Publications and source records attributed to Mortreux, F..

8 recordsLinked to original sources

bioRxiv2024

Induction of tolerogenicity following a molecular dialogue between HTLV-1-infected T cells and dendritic cells

Manipulation of immune cell functions, independently of direct infection of these cells, emerges as a key process in viral pathophysiology. Chronic infection by Human T-cell Leukemia Virus type 1 (HTLV-1) is associated with immune dysfunctions, including misdirected responses of dendritic cells (DCs). Here, we interrogate the ability of transformed HTLV-1-infected T cells to manipulate human DC functions. We show that exposure to transformed HTLV-1-infected T cells induces a biased and peculiar transcriptional signature in monocyte-derived DCs, associated with an inefficient maturation and a poor responsiveness to subsequent stimulation by a TLR4 agonist. This poor responsiveness is also associated with a unique transcriptional landscape characterized by a set of genes whose expression is either conferred, impaired or abolished by HTLV-1 pre-exposure. Induction of this functional impairment requires several hours of coculture with transformed HTLV-1-infected cells, and associated mechanisms driven by viral capture, cell-cell contacts, and soluble mediators. Altogether, this cross-talk between infected T cells and DCs illustrate how HTLV-1 might co-opt communications between cells to induce a unique local tolerogenic immune microenvironment suitable for its own persistence. SignificanceChronic viral infection is associated with an escape from immune surveillance. This may rely on the induction of inappropriate DC responses, which can contribute to immunopathology. Immune dysfunctions have been repeatedly reported in people living with Human T-cell Leukemia Virus type 1 (HTLV-1), years before fatal clinical symptom onset, including misdirected responses of dendritic cells (DCs). Here, we report that HTLV-1-infected T cells actively manipulate neighboring, uninfected MDDC functions by rewiring their transcriptional response, leading to a biased, pro-tolerogenic responsiveness in MDDCs, induced by the bidirectional release of soluble mediators, in cooperation with mechanisms dependent on cell-cell contacts. This cross-talk illustrate how HTLV-1 might co-opt communications between cells to induce a local tolerogenic immune microenvironment suitable for its own persistence

microbiology↗

bioRxiv2024

The MYCN oncoprotein and helicases DDX17 and DDX5 have opposite effects on the production of chimeric transcripts in neuroblastoma cells

DEAD box helicases DDX17 and DDX5 control the termination of transcription and the associated cleavage of the 3 end of transcripts. Here we show that the transcriptional readthrough induced by their depletion in neuroblastoma cells also results in increased production of chimeric transcripts from tandemly oriented genes. Analysis of neuroblastoma tumours in which chimeric transcripts are abundant revealed that low expression of the DDX17 and DDX5 genes is associated with poor overall patient survival. Low DDX17 expression is also significantly associated with high-risk tumours and is inversely correlated with MYCN oncogene amplification, suggesting a link between these two factors. We demonstrate that changes in MYCN expression do not affect the expression of either helicase, but alter transcription termination leading to the production of chimeric transcripts. We provide evidence that MYCN acts on termination through its direct binding to the 3 region of genes and that it interacts with DDX17, suggesting that it may inhibit the activity of the helicase. Collectively, our work reveals a novel function of MYCN in transcription termination and suggests that the deregulation of MYCN and DDX17/DDX5 expression in neuroblastoma may lead to the expression of non-canonical and potentially harmful RNA molecules.

molecular biology↗

bioRxiv2023

Gene-to-Gene Coordinated Regulation of Transcription and Alternative splicing by 3D Chromatin Remodeling upon NF-κB activation

The p65/RelA factor of NF-{kappa}B plays a pivotal role in coordinating gene expression in response to diverse stimuli, including viral infections. At the chromatin level, p65/RelA regulates gene transcription and alternative splicing (AS) through promoter enrichment and genomic exon occupancy, respectively. However, the mechanisms underlying the coordination of these processes across distinct genes remain elusive. In this study, we employed the HTLV-1 Tax oncoprotein, a potent activator of NF-{kappa}B, to investigate the integrative relationship between 3D chromatin architecture, NF-{kappa}B-regulated transcription and AS. Our analysis revealed that Tax induces a pronounced reorganization of the 3D genome, resulting in the formation of multigene complexes that comprise genes regulated either transcriptionally or through AS. Notably, we found that the Tax-induced gene-gene contact between the two master genes NFKBIA and RELA is associated with their differential regulation in gene expression and AS, respectively. Through dCas9-mediated approaches, we demonstrated that NFKBIA-RELA interaction is required for AS regulation and is caused by an intragenic enrichment of p65/RelA on RELA. Our findings shed light on new regulatory mechanisms upon HTLV-1 Tax and underscore the integral role of p65/RelA in coordinated regulation of NF-{kappa}B-responsive genes at both transcriptional and AS levels in the context of the 3D genome.

molecular biology↗

bioRxiv2023

SplicingLore: a web resource for studying the regulation of cassette exons by human splicing factors

One challenge faced by scientists from the alternative RNA splicing field is to decode the cooperative or antagonistic effects of splicing factors to understand and eventually predict splicing outcomes on a genome-wide scale. In this manuscript, we introduce SplicingLore, an open access database and web resource that help to fill this gap in a straightforward manner. The database contains a collection of RNA-seq-derived lists of alternative exons regulated by a total of 75 different splicing factors. All datasets were processed in a standardized manner, ensuring valid comparisons and correlation analyses. The user can easily retrieve a factor-specific set of differentially included exons from the database, or provide a list of exons and search which splicing factor(s) control(s) their inclusion. Our simple workflow is fast and easy to run, and it ensures a reliable calculation of correlation scores between the tested datasets. As a proof of concept, we predicted and experimentally validated a novel functional cooperation between the RNA helicases DDX17 and DDX5 and the HNRNPC protein. SplicingLore is available at https://splicinglore.ens-lyon.fr/.

genomics↗

bioRxiv2021

The viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape

While viral infections are known to hijack the transcription and translation of the host cell, the extent to which encoded viral proteins coordinate these perturbations remains unclear. Here we demonstrate that the oncoviral proteins Tax and HBZ interact with specific components of the spliceosome machinery, including the U2 auxiliary factor large subunit (U2AF2), and the complementary factor for APOBEC-1 (A1CF), respectively. Tax and HBZ perturb the splicing landscape in T-cells by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia (ATL) patients, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinately used by Tax and HBZ to reprogram the transcriptome. HighlightsO_LITax and HBZ interact with RNA-binding proteins as well as transcription factors C_LIO_LIHTLV-1 encoded proteins Tax and HBZ alter the splicing landscape in T-cells C_LIO_LITax and HBZ expression affect alternative splicing of 33 and 63 cancer genes, respectively C_LIO_LIOpposing roles for Tax and HBZ in deregulation of gene expression C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/427104v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@b5f6f0org.highwire.dtl.DTLVardef@6725b3org.highwire.dtl.DTLVardef@1dc32fborg.highwire.dtl.DTLVardef@19728c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2019

Intragenic recruitment of NF-κB drives alternative splicing modifications upon activation by the viral oncogene TAX of HTLV-1.

The chronic NF-{kappa}B activation in inflammation and cancer has long been linked to persistent activation of NF-{kappa}B responsive gene promoters. However, NF-{kappa}B factors such as RELA also massively bind to gene bodies. Here, we demonstrate that the recruitment of RELA to intragenic regions regulates alternative splicing upon activation of NF-{kappa}B by the viral oncogene TAX of HTLV-1. Integrative analysis of RNA splicing and chromatin occupancy, combined with chromatin tethering assays, demonstrate that DNA-bound RELA interacts with and recruits the splicing regulator DDX17 in a NF-kB activation-dependent manner, leading to alternative splicing of target exons thanks to DDX17 RNA helicase activity. This NF-kB/DDX17 axis accounts for a major part of the TAX-induced alternative splicing landscape that mainly affects genes involved in oncogenic pathways. Collectively, our results demonstrate a physical and direct involvement of NF-{kappa}B in alternative splicing regulation, which significantly revisits our knowledge of HTLV-1 pathogenesis and other NF-{kappa}B-related diseases.

molecular biology↗

bioRxiv2019

Interplay between gene nucleotide composition bias and splicing

To characterize the rules governing exon recognition during splicing, we analysed dozens of RNA-seq datasets and identified ~3,200 GC-rich exons and ~4,000 AT-rich exons whose inclusion depends on different sets of splicing factors. We show that GC-rich exons have predicted RNA secondary structures at 5-ss, and are dependent on U1 snRNP-associated proteins. In contrast, AT-rich exons have a large number of branchpoints and SF1-or U2AF2-binding sites and are dependent on U2 snRNP-associated proteins. Nucleotide composition bias also influences local chromatin organization, with consequences for exon recognition during splicing. As the GC content of exons correlates with that of their hosting genes, isochores and topologically-associated domains, we propose that regional nucleotide composition bias leaves a local footprint at the exon level and induces constraints during splicing that can be alleviated by local chromatin organization and recruitment of specific splicing factors. Therefore, nucleotide composition bias establishes a direct link between genome organization and local regulatory processes, like alternative splicing.

molecular biology↗

bioRxiv2018

Interplay between coding and exonic splicing regulatory sequences

The inclusion of exons during the splicing process depends on the binding of splicing factors to short low-complexity regulatory sequences. The relationship between exonic splicing regulatory sequences and coding sequences is still poorly understood. We demonstrate that exons that are coregulated by any splicing factor share a similar nucleotide composition bias. We next demonstrate that coregulated exons preferentially code for amino acids with similar physicochemical properties because of the non-randomness properties of the genetic code. Indeed, amino acids sharing physicochemical properties correspond to codons that have the same nucleotide composition bias. These observations reveal an unanticipated bidirectional interplay between the physicochemical features encoded by exons and exon splicing regulation by splicing factors. We propose that the splicing regulation of an exon by a splicing factor is tightly interconnected with the physicochemical properties of the exon-encoded protein domain depending on the splicing-factor affinity for specific nucleotides.

genomics↗