Biology subjects

Gendron, P.

Publications and source records attributed to Gendron, P..

5 recordsLinked to original sources

bioRxiv2025

Nuclear RNA cap-chaperones eIF4E and NCBP2 govern distinct fates for 1000s of mRNAs uncovering an unexpected regulatory point in gene expression

mRNA processing constitutes a series of steps in the nucleus to generate mature mRNAs that can be translated into protein. This relies on the methyl-7-guanosine (m7G) "cap" on the 5end of mRNAs which is bound by the nuclear cap-binding protein NCBP2 with its cofactor NCBP1. The NCBP1/2 complex chaperones capped mRNA through these processing steps. NCBP2 is considered the sole nuclear cap-binding factor and thus its cap-chaperone role is thought to be a constitutive, housekeeping activity. However, another cap-binding protein, the eukaryotic translation initiation factor eIF4E, is also found in the nucleus. Two cap-binding factors co-existing in the nucleus intimate an undiscovered regulatory point in gene expression or, alternatively, redundancy to ensure gene expression fidelity. Consistent with the former possibility, eIF4E and NCBP2 drove distinct gene expression, transcriptomic, and splicing signatures impacting [~]2500 transcripts involved in distinct biological programmes with only [~]360 transcripts in common and of these only 79 common splicing events. Thus, each cap-chaperone designates distinct mRNA populations for specific processing revealing a new step in gene expression. We denote this mRNA specification of cap-chaperones (SOCCS). We uncovered multiple molecular mechanisms that contribute to SOCCS: distinct spatial localization of eIF4E and NCBP2 within the nucleus, identification of sequence motifs within targeted mRNAs segregated by eIF4E or NCBP2 sensitivity, distinct protein partners for these cap-chaperones and differential impacts on the production of key spliceosome components e.g. U2AF1, PRP31, SF3B1 and SNRNP200 indicative of distinct transcriptomic landscapes produced by eIF4E or NCBP2 overexpression. In all, the realization that multiple cap-binding proteins coexist in the nucleus led us to identify an unexpected gene-expression regulatory point which engaged distinct biological programmes.

genetics↗

bioRxiv2023

Transposable elements regulate thymus development and function

Transposable elements (TE) are repetitive sequences representing [~]45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTEC). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multi-omic analyses of TEs in human and mouse thymic cells to elucidate their role in T cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDC). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN LJ/{beta}. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.

immunology↗

bioRxiv2022

BamQuery: a proteogenomic tool for the genome-wide exploration of the immunopeptidome

MHC-I-associated peptides (MAPs) derive from selective yet highly diverse genomic regions, including allegedly non-protein-coding sequences, such as endogenous retroelements (EREs). Quantifying canonical (exonic) and non-canonical MAPs-encoding RNA expression in malignant and benign cells is critical for identifying tumor antigens (TAs) but represents a challenge for immunologists. We present BamQuery, a computational tool attributing an exhaustive RNA expression to MAPs of any origin (exon, intron, UTR, intergenic) from bulk and single-cell RNA-sequencing data. We show that non-canonical MAPs (including TAs) can derive from multiple different genomic regions (up to 35,343 for EREs), abundantly expressed in normal tissues. We also show that supposedly tumor-specific mutated MAPs, viral MAPs, and MAPs derived from proteasomal splicing can arise from different unmutated non-canonical genomic regions. The genome-wide approach of BamQuery allows comprehensive mapping of all MAPs in healthy and cancer tissues. BamQuery can also help predict MAP immunogenicity and identify safe and actionable TAs.

immunology↗

bioRxiv2021

The eukaryotic translation initiation factor eIF4E reprogrammes the splicing machinery anddrives alternative splicing

Aberrant RNA splicing contributes to the pathogenesis of many malignancies including Acute Myeloid Leukemia (AML). While mutation is the best described mechanism underpinning aberrant splicing, recent studies show that predictions based on mutations alone likely underestimate the extent of this dysregulation. Here, we show that elevation of the eukaryotic translation initiation factor eIF4E reprogrammes splicing of nearly a thousand RNAs in model cell lines. Further, in AML patient specimens which did not harbour known splice factor mutations, [~]4000 transcripts were differentially spliced based on eIF4E levels and this was associated with poor prognosis. Inhibition of eIF4E in cell lines reverted the eIF4E-dependent splice events examined. Splicing targets of eIF4E act in biological processes consistent with its role in malignancy. This altered splicing program likely arose from eIF4E-dependent increases in the production of spliceosome components including SF3B1 and U2AF1 which are frequently mutated in AML. Notably, eIF4E did not drive mutation of these factors, only their production. eIF4E also physically associated with many splice factors including SF3B1, U2AF1, and UsnRNAs. Interestingly, eIF4E interacted with both pre-mRNA splicing substrates as well as the resulting product RNAs suggesting that eIF4E could chaperone RNAs throughout splicing as well as other aspects of post-splicing transcript regulation. Importantly, many eIF4E-dependent splice events differed from those arising from splice factor mutation and were more extensive highlighting that these splicing profiles arise from distinct, but potentially overlapping, mechanisms. In all, our studies provide a paradigm for how dysregulation of a single factor, eIF4E, can reprogramme splicing.

cancer biology↗

bioRxiv2018

Target variant detection in leukemia using unaligned RNA-Seq reads

Mutations identified in each Acute Myeloid Leukemia (AML) patients are useful for prognosis and to select targeted therapies. Detection of such mutations by the analysis of Next-Generation Sequencing (NGS) data requires a computationally intensive read mapping step and application of several variant calling methods. Targeted mutation identification drastically shifts the usual tradeoff between accuracy and performance by concentrating all computations over a small portion of sequence space. Here, we present km, an efficient approach leveraging k-mer decomposition of reads to identify targeted mutations. Our approach is versatile, as it can detect single-base mutations, several types of insertions and deletions, as well as fusions. We used two independent AML cohorts (The Cancer Genome Atlas and Leucegene), to show that mutation detection by km is fast, accurate and mainly limited by sequencing depth. Therefore, km allows to establish fast diagnostics from NGS data, and could be suitable for clinical applications.

bioinformatics↗