Biology subjects

Duchaine, T.

Publications and source records attributed to Duchaine, T..

7 recordsLinked to original sources

bioRxiv2026

A map of RBP-miRNA regulatory connections for deciphering the mechanisms of transcriptome remodeling in cancer

Micro-RNAs (miRNAs) are key post-transcriptional regulators of gene expression that influence cancer progression and outcome. Whereas transcriptional dysregulation of miRNA abundance underlies abnormal functionality of some miRNAs in cancer, emerging data points to RNA-binding proteins (RBPs) as prominent post-transcriptional regulators of miRNA activity. Here, by modelling the regulon activities of well-characterized miRNA families in RNA-seq data of a comprehensive collection of RBP inhibition experiments, human cell lines and tissues, we report a map of regulatory connections between 34 RBPs and 28 miRNAs. Furthermore, through a global analysis of the abundance as well as the activity of miRNAs in thousands of tumor and control samples from 17 human cancers, we show that RBP-driven regulation of miRNA activity is common in tumors and contributes to the heterogeneity in miRNA activity profiles. We uncover a set of RBPs that regulate the activity of tumor-suppressor and oncogenic miRNAs, including miR-29-3p, miR-17-5p and miR-19-3p. Of particular interest, we describe a pan-cancer negative regulatory role for DDX55 on the activity of the miR-29-3p family, a critical miRNA family with tumor suppressor functions that is involved in most human cancers. Our functional studies confirm that DDX55 inhibition restores the gene-silencing activity of miR-29-3p and reduces cancer cell viability. Overall, our study provides the first pan-cancer investigation of functional regulatory connections between RBPs and miRNAs, and highlights RBPs whose interventional modulation may serve as a new approach to reprogram abnormal miRNA activities in cancer.

genomics↗

bioRxiv2024

EDC-3 and EDC-4 Regulate Embryonic mRNA Clearance and Biomolecular Condensate Specialization

Animal development is dictated by the selective and timely decay of mRNAs in developmental transitions, but the impact of mRNA decapping scaffold proteins in development is unknown. This study unveils the roles and interactions of the DCAP-2 decapping scaffolds EDC-3 and EDC-4 in the embryonic development of C. elegans. EDC-3 facilitates the timely removal of specific embryonic mRNAs, including cgh-1, car-1, and ifet-1 by reducing their expression, and preventing excessive accumulation of DCAP-2 condensates in somatic cells. We further uncover a novel role for EDC-3 in defining the boundaries between P-bodies, germ granules, and stress granules. Lastly, we show that EDC-4 counteracts EDC-3 and engenders the assembly of DCAP-2 with the GID (CTLH) complex, a ubiquitin ligase involved in maternal-to-zygotic transition (MZT). Our findings support a model wherein multiple RNA decay mechanisms temporally partake in the clearance of maternal and zygotic mRNAs throughout embryonic development.

molecular biology↗

bioRxiv2023

Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction

Viruses commonly interfere with the function of the eukaryotic translation initiation factor 4G1 (eIF4G1), a pivotal factor in the recruitment of the eIF3 complex and ribosome to the mRNA. This results in the inhibition of general host protein synthesis and redirecting ribosomes toward viral mRNAs. Certain viruses also selectively repress the translation of mRNAs involved in the host antiviral response. GIGYF2 and its interacting cap-binding protein 4EHP enable the transcript-specific repression of mRNA translation mediated by microRNAs and RNA-binding proteins (RBPs). RNA viruses, such as SARS-CoV-2, exploit the GIGYF2/4EHP complex to selectively repress the translation of transcripts such as Ifnb1 mRNA, which encodes the antiviral cytokine Interferon {beta} (IFN-{beta}). Herein, we reveal that GIGYF1, a paralogue of GIGYF2, robustly represses cellular mRNA translation through a distinct mechanism independent of 4EHP. Upon recruitment to a target mRNA by RBPs, the C-terminal region of GIGYF1 binds to subunits of eIF3 at the interaction interface of eIF3-eIF4G1. This disrupts binding of eIF3 to eIF4G1, resulting in mRNA-specific translational repression. This mechanism exerts profound influences on the host cells response to viral infection. Depletion of GIGYF1 induces a robust immune response by derepressing Ifnb1 mRNA translation. Overall, our study highlights a unique mechanism of translational regulation by GIGYF1 that involves sequestering eIF3 and abrogating its binding to eIF4G1. This mechanism can be utilized by RBPs that interact with GIGYF1 to specifically repress the translation of their target mRNAs, significantly affecting critical biological processes, including host-pathogen interactions.

cell biology↗

bioRxiv2023

SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression

microRNAs (miRNAs) inhibit mRNA translation initiation by recruiting the GIGYF2/4EHP translation repressor complex to the mRNA 5 cap structure. Viruses utilise miRNAs to impair the host antiviral immune system and facilitate viral infection by expressing their own miRNAs or co-opting cellular miRNAs. We recently reported that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encoded non-structural protein 2 (NSP2) interacts with GIGYF2. This interaction is critical for blocking translation of the Ifn1-b mRNA that encodes the cytokine Interferon-{beta}, and thereby impairs the host antiviral immune response. However, it is not known whether NSP2 also affects miRNA-mediated silencing. Here, we demonstrate the pervasive augmentation of the miRNA-mediated translational repression of cellular mRNAs by NSP2. We show that NSP2 interacts with Argonaute 2, the core component of the miRNA-Induced Silencing Complex (miRISC) and enhances the translational repression mediated by natural miRNA binding sites in the 3 UTR of cellular mRNAs. Our data reveal an additional layer of the complex mechanism by which SARS-CoV-2 and likely other coronaviruses manipulate the host gene expression program through co-opting the host miRNA-mediated silencing machinery.

cell biology↗

bioRxiv2022

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a novel mechanism by which the SARS-CoV-2 virus co-opts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-{beta}. We reveal that the SARS-CoV-2 encoded Non-Structural Protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-{beta} production, leading to reduced viral infection. Our findings reveal a new target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

microbiology↗

bioRxiv2021

Distinct, opposing functions for CFIm59 and CFIm68 in mRNA alternative polyadenylation of Pten and in the PI3K/Akt signalling cascade

The precise maintenance of PTEN dosage is crucial for tumor suppression across a wide variety of cancers. Post-transcriptional regulation of Pten heavily relies on regulatory elements encoded by its 3UTR. We previously reported the important diversity of 3UTR isoforms of Pten mRNAs produced through alternative polyadenylation (APA). Here, we reveal the direct regulation of Pten APA by the mammalian cleavage factor I (CFIm) complex, which in turn contributes to PTEN protein dosage. CFIm consists of the UGUA-binding CFIm25 and APA regulatory subunits CFIm59 or CFIm68. Deep sequencing analyses of perturbed (KO and KD) cell lines uncovered the differential regulation of Pten APA by CFIm59 and CFIm68 and further revealed that their divergent functions have widespread impact for APA in transcriptomes. Differentially regulated genes include numerous factors within the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway that PTEN counter-regulates. We further reveal a stratification of APA dysregulation among a subset of PTEN-driven cancers, with recurrent alterations among PI3K/Akt pathway genes regulated by CFIm. Our results refine the transcriptome selectivity of the CFIm complex in APA regulation, and the breadth of its impact in PTEN-driven cancers.

biochemistry↗

bioRxiv2021

Novel LOTUS-domain proteins are organizational hubs that recruit C. elegans Vasa to germ granules

We describe MIP-1 and MIP-2, novel paralogous C. elegans germ granule components that interact with the intrinsically disordered MEG-3 protein. These proteins promote P granule condensation, form granules independently of MEG-3 in the postembryonic germ line, and balance each other in regulating P granule growth and localization. MIP-1 and MIP-2 each contain two LOTUS domains and intrinsically disordered regions and form homo- and heterodimers. They bind and anchor the Vasa homolog GLH-1 within P granules and are jointly required for coalescence of MEG-3, GLH-1, and PGL proteins. Animals lacking MIP-1 and MIP-2 show temperature-sensitive embryonic lethality, sterility, and mortal germ lines. Germline phenotypes include defects in stem cell self-renewal, meiotic progression, and gamete differentiation. We propose that these proteins serve as scaffolds and organizing centers for ribonucleoprotein networks within P granules that help recruit and balance essential RNA processing machinery to regulate key developmental transitions in the germ line.

cell biology↗