Skip to content. | Skip to navigation

Personal tools

You are here: Home / Publications / Publications


The last 50 bibliographies

Loss of SET1/COMPASS methyltransferase activity reduces lifespan and fertility in Caenorhabditis elegans.

Author(s) : Caron M, Gely L, Garvis S, Adrait A, Couté Y, Palladino F, Fabrizio P,
Journal : Life Sci Alliance
Changes in histone post-translational modifications are associated with agingthrough poorly defined mechanisms. Histone 3 lysine 4 (H3K4) methylation atpromoters is deposited by SET1 family methyltransferases acting within conservedmultiprotein complexes known as COMPASS. Previous work yielded conflicting resultsabout the requirement for H3K4 methylation during aging. Here, we reassessed therole of SET1/COMPASS-dependent H3K4 methylation in Caenorhabditis elegans lifespanand fertility by generating set-2(syb2085) mutant animals that express acatalytically inactive form of SET-2, the C. elegans SET1 homolog. We show thatset-2(syb2085) animals retain the ability to form COMPASS, but have a marked globalloss of H3K4 di- and trimethylation (H3K4me2/3). Reduced H3K4 methylation wasaccompanied by loss of fertility, as expected; however, in contrast to earlierstudies, set-2(syb2085) mutants displayed a significantly shortened, not extended,lifespan and had normal intestinal fat stores. Other commonly used set-2 mutantswere also short-lived, as was a cfp-1 mutant that lacks the SET1/COMPASSchromatin-targeting component. These results challenge previously held views andestablish that WT H3K4me2/3 levels are essential for normal lifespan in C. elegans.

Altered splicing of ATG16-L1 mediates acquired resistance to tyrosine kinase inhibitors of EGFR by blocking autophagy in non-small cell lung cancer.

Author(s) : Hatat A, Benoit-Pilven C, Pucciarelli A, de Fraipont F, Lamothe L, Perron P, Rey A, Levra M, Toffart A, Auboeuf D, Eymin B, Gazzeri S,
Journal : Mol Oncol
Despite the initial efficacy of using tyrosine kinase inhibitors of epidermalgrowth factor receptors (EGFR-TKIs) for treating patients with non-small celllung cancer (NSCLC), resistance inevitably develops. Recent studies highlight alink between alternative splicing and cancer drug response. Therefore, we aimedto identify deregulated splicing events that play a role in resistance toEGFR-TKI. By using RNA sequencing, reverse-transcription PCR (RT-PCR), and RNAinterference, we showed that overexpression of a splice variant of the autophagicgene ATG16-L1 that retains exon 8 and encodes the β-isoform of autophagy-relatedprotein 16-1 (ATG16-L1 β) concurs acquired resistance to EGFR-TKI in NSCLC cells.Using matched biopsies, we found increased levels of ATG16-L1 β at the time ofprogression in 3 of 11 NSCLC patients treated with EGFR-TKI. Mechanistically,gefitinib-induced autophagy was impaired in resistant cells that accumulatedATG16-L1 β. Neutralization of ATG16-L1 β restored autophagy in response togefitinib, induced apoptosis, and inhibited the growth of in ovo tumorxenografts. Conversely, overexpression of ATG16-L1 β in parental sensitive cellsprevented gefitinib-induced autophagy and increased cell survival. These resultssupport a role of defective autophagy in acquired resistance to EGFR-TKIs andidentify splicing regulation of ATG16-L1 as a therapeutic vulnerability thatcould be explored for improving EGFR-targeted cancer therapy.

RNA helicase-dependent gene looping impacts messenger RNA processing.

Author(s) : Terrone S, Valat J, Fontrodona N, Giraud G, Claude J, Combe E, Lapendry A, Polvèche H, Ameur L, Duvermy A, Modolo L, Bernard P, Mortreux F, Auboeuf D, Bourgeois C,
Journal : Nucleic Acids Res
DDX5 and DDX17 are DEAD-box RNA helicase paralogs which regulate several aspectsof gene expression, especially transcription and splicing, through incompletelyunderstood mechanisms. A transcriptome analysis of DDX5/DDX17-depleted humancells confirmed the large impact of these RNA helicases on splicing and revealeda widespread deregulation of 3' end processing. In silico analyses andexperiments in cultured cells showed the binding and functional contribution ofthe genome organizing factor CTCF to chromatin sites at or near a subset ofDDX5/DDX17-dependent exons that are characterized by a high GC content and a highdensity of RNA Polymerase II. We propose the existence of an RNAhelicase-dependent relationship between CTCF and the dynamics of transcriptionacross DNA and/or RNA structured regions, that contributes to the processing ofinternal and terminal exons. Moreover, local DDX5/DDX17-dependent chromatin loopsspatially connect RNA helicase-regulated exons with their cognate promoter, andwe provide the first direct evidence that de novo gene looping modifiesalternative splicing and polyadenylation. Overall our findings uncover the impactof DDX5/DDX17-dependent chromatin folding on pre-messenger RNA processing.

Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes

Author(s) : Dincã D, Lallemant L, González-Barriga A, Cresto N, Braz S, Sicot G, Pillet L, Polvèche H, Magneron P, Huguet-Lachon A, Benyamine H, Azotla-Vilchis C, Agonizantes-Juárez L, Tahraoui-Bories J, Martinat C, Hernández-Hernández O, Auboeuf D, Rouach N, Bourgeois C, Gourdon G, Gomes-Pereira M,
Journal : Nat Commun
Brain dysfunction in myotonic dystrophy type 1 (DM1), the prototype of toxic RNAdisorders, has been mainly attributed to neuronal RNA misprocessing, while littleattention has been given to non-neuronal brain cells. Here, using a transgenicmouse model of DM1 that expresses mutant RNA in various brain cell types(neurons, astroglia, and oligodendroglia), we demonstrate that astrocytes exhibitimpaired ramification and polarization in vivo and defects in adhesion,spreading, and migration. RNA-dependent toxicity and phenotypes are also found inhuman transfected glial cells. In line with the cell phenotypes, molecularanalyses reveal extensive expression and accumulation of toxic RNA in astrocytes,which result in RNA spliceopathy that is more severe than in neurons. Astrocytemissplicing affects primarily transcripts that regulate cell adhesion,cytoskeleton, and morphogenesis, and it is confirmed in human brain tissue. Ourfindings demonstrate that DM1 impacts astrocyte cell biology, possiblycompromising their support and regulation of synaptic function.

Titration of Apparent In-Cellula Affinities of Protein-Protein Interactions.

Author(s) : Cluet D, Vergier B, Levy N, Dehau L, Thurman A, Amri I, Spichty M,
Journal : Chembiochem
A genetic assay permits simultaneous quantification of two interacting proteinsand their bound fraction at the single-cell level using flow cytometry. Apparentin-cellula affinities of protein-protein interactions can be extracted from theacquired data through a titration-like analysis. The applicability of thisapproach is demonstrated on a diverse set of interactions with proteins fromdifferent families and organisms and with in-vitro dissociation constants rangingfrom picomolar to micromolar.

Three classes of epigenomic regulators converge to hyperactivate the essential maternal gene deadhead within a heterochromatin mini-domain.

Author(s) : Torres-Campana D, Horard B, Denaud S, Benoit G, Loppin B, Orsi G,
Journal : PLoS Genet
The formation of a diploid zygote is a highly complex cellular process that isentirely controlled by maternal gene products stored in the egg cytoplasm. Thishighly specialized transcriptional program is tightly controlled at the chromatinlevel in the female germline. As an extreme case in point, the massive and specificovarian expression of the essential thioredoxin Deadhead (DHD) is criticallyregulated in Drosophila by the histone demethylase Lid and its partner, the histonedeacetylase complex Sin3A/Rpd3, via yet unknown mechanisms. Here, we identified Snr1and Mod(mdg4) as essential for dhd expression and investigated how these epigenomiceffectors act with Lid and Sin3A to hyperactivate dhd. Using Cut&Run chromatinprofiling with a dedicated data analysis procedure, we found that dhd isintriguingly embedded in an H3K27me3/H3K9me3-enriched mini-domain flanked by DNAregulatory elements, including a dhd promoter-proximal element essential for itsexpression. Surprisingly, Lid, Sin3a, Snr1 and Mod(mdg4) impact H3K27me3 and thisregulatory element in distinct manners. However, we show that these effectorsactivate dhd independently of H3K27me3/H3K9me3, and that dhd remains silent in theabsence of these marks. Together, our study demonstrates an atypical and criticalrole for chromatin regulators Lid, Sin3A, Snr1 and Mod(mdg4) to triggertissue-specific hyperactivation within a unique heterochromatin mini-domain.

3DGenBench: a web-server to benchmark computational models for 3D Genomics.

Author(s) : Belokopytova P, Viesná E, Chiliński M, Qi Y, Salari H, Di Stefano M, Esposito A, Conte A, Chiariello A, Teif V, Plewczynski D, Zhang B, Jost D, Fishman V,
Journal : Nucleic Acids Res
Modeling 3D genome organisation has been booming in the last years thanks to theavailability of experimental datasets of genomic contacts. However, the field iscurrently missing the standardisation of methods and metrics to comparepredictions and experiments. We present 3DGenBench, a web server available at, that allows benchmarking computational modelsof 3D Genomics. The benchmark is performed using a manually curated dataset of 39capture Hi-C profiles in wild type and genome-edited mouse cells, and fivegenome-wide Hi-C profiles in human, mouse, and Drosophila cells. 3DGenBenchperforms two kinds of analysis, each supplied with a specific scoring module thatcompares predictions of a computational method to experimental data using severalmetrics. With 3DGenBench, the user obtains model performance scores, allowing anunbiased comparison with other models. 3DGenBench aims to become a reference webserver to test new 3D genomics models and is conceived as an evolving platformwhere new types of analysis will be implemented in the future.

FORK-seq: Single-Molecule Profiling of DNA Replication.

Author(s) : Hennion M, Theulot B, Arbona J, Audit B, Hyrien O,
Journal : Methods Mol Biol
Most genome replication mapping methods profile cell populations, maskingcell-to-cell heterogeneity. Here, we describe FORK-seq, a nanopore sequencingmethod to map replication of single DNA molecules at 200 nucleotide resolutionusing a nanopore current interpretation tool allowing the quantification of BrdUincorporation. Along pulse-chased replication intermediates from Saccharomycescerevisiae, we can orient replication tracks and reproduce population-basedreplication directionality profiles. Additionally, we can map individualinitiation and termination events. Thus, FORK-seq reveals the full extent ofcell-to-cell heterogeneity in DNA replication.

Genome-wide mapping of individual replication fork velocities using nanopore sequencing.

Author(s) : Theulot B, Lacroix L, Arbona J, Millot G, Jean E, Cruaud C, Pellet J, Proux F, Hennion M, Engelen S, Lemainque A, Audit B, Hyrien O, Le Tallec B,
Journal : Nat Commun
Little is known about replication fork velocity variations along eukaryoticgenomes, since reference techniques to determine fork speed either provide nosequence information or suffer from low throughput. Here we presentNanoForkSpeed, a nanopore sequencing-based method to map and extract the velocityof individual forks detected as tracks of the thymidine analoguebromodeoxyuridine incorporated during a brief pulse-labelling of asynchronouslygrowing cells. NanoForkSpeed retrieves previous Saccharomyces cerevisiae meanfork speed estimates (≈2 kb/min) in the BT1 strain exhibiting highly efficientbromodeoxyuridine incorporation and wild-type growth, and precisely quantifiesspeed changes in cells with altered replisome progression or exposed tohydroxyurea. The positioning of >125,000 fork velocities provides a genome-widemap of fork progression based on individual fork rates, showing a uniform forkspeed across yeast chromosomes except for a marked slowdown at known pausingsites.

Prognostic impact of ABCA3 expression in adult and pediatric acute myeloid leukemia: an ALFA-ELAM02 joint study

Author(s) : Ceraulo A, Lapillonne H, Cheok M, Preudhomme C, Dombret H, Terré C, Lambert J, Leverger G, Bertrand Y, Mortreux F, Wattel E,
Journal : Blood Adv