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Entropy Measures Quantify Global Splicing Disorders in Cancer

William Ritchie, Samuel Granjeaud, Denis Puthier, Daniel Gautheret, Manuel Ares
2008 PLoS Computational Biology  
Most mammalian genes are able to express several splice variants in a phenomenon known as alternative splicing. Serious alterations of alternative splicing occur in cancer tissues, leading to expression of multiple aberrant splice forms. Most studies of alternative splicing defects have focused on the identification of cancer-specific splice variants as potential therapeutic targets. Here, we examine instead the bulk of non-specific transcript isoforms and analyze their level of disorder using
more » ... measure of uncertainty called Shannon's entropy. We compare isoform expression entropy in normal and cancer tissues from the same anatomical site for different classes of transcript variations: alternative splicing, polyadenylation, and transcription initiation. Whereas alternative initiation and polyadenylation show no significant gain or loss of entropy between normal and cancer tissues, alternative splicing shows highly significant entropy gains for 13 of the 27 cancers studied. This entropy gain is characterized by a flattening in the expression profile of normal isoforms and is correlated to the level of estimated cellular proliferation in the cancer tissue. Interestingly, the genes that present the highest entropy gain are enriched in splicing factors. We provide here the first quantitative estimate of splicing disruption in cancer. The expression of normal splice variants is widely and significantly disrupted in at least half of the cancers studied. We postulate that such splicing disorders may develop in part from splicing alteration in key splice factors, which in turn significantly impact multiple target genes.
doi:10.1371/journal.pcbi.1000011 pmid:18369415 pmcid:PMC2268240 fatcat:2rijh3uugvfoxiqkeia2x64skm

RNA-Guided Genomic Localization of H2A.L.2 Histone Variant

Naghmeh Hoghoughi, Sophie Barral, Sandrine Curtet, Florent Chuffart, Guillaume Charbonnier, Denis Puthier, Thierry Buchou, Sophie Rousseaux, Saadi Khochbin
2020 Cells  
The molecular basis of residual histone retention after the nearly genome-wide histone-to-protamine replacement during late spermatogenesis is a critical and open question. Our previous investigations showed that in postmeiotic male germ cells, the genome-scale incorporation of histone variants TH2B-H2A.L.2 allows a controlled replacement of histones by protamines to occur. Here, we highlight the intrinsic ability of H2A.L.2 to specifically target the pericentric regions of the genome and
more » ... s why pericentric heterochromatin is a privileged site of histone retention in mature spermatozoa. We observed that the intranuclear localization of H2A.L.2 is controlled by its ability to bind RNA, as well as by an interplay between its RNA-binding activity and its tropism for pericentric heterochromatin. We identify the H2A.L.2 RNA-binding domain and demonstrate that in somatic cells, the replacement of H2A.L.2 RNA-binding motif enhances and stabilizes its pericentric localization, while the forced expression of RNA increases its homogenous nuclear distribution. Based on these data, we propose that the specific accumulation of RNA on pericentric regions combined with H2A.L.2 tropism for these regions are responsible for stabilizing H2A.L.2 on these regions in mature spermatozoa. This situation would favor histone retention on pericentric heterochromatin.
doi:10.3390/cells9020474 pmid:32085641 pmcid:PMC7072763 fatcat:xne6qties5fffofljdclulnim4

Widespread Enhancer Activity from Core Promoters

Alejandra Medina-Rivera, David Santiago-Algarra, Denis Puthier, Salvatore Spicuglia
2018 TIBS -Trends in Biochemical Sciences. Regular ed  
doi:10.1016/j.tibs.2018.03.004 pmid:29673772 fatcat:lkrorylannfohkbmusjwl4utfi

Rôle des longs ARN non codants dans le développement normal et pathologique

Ève-Lyne Mathieu, Mohamed Belhocine, Lan T.M. Dao, Denis Puthier, Salvatore Spicuglia
2014 M S.Médecine Sciences  
doi:10.1051/medsci/20143008018 pmid:25174757 fatcat:7zzluurxkfcu3o4ut5lqbu4a5a

OLOGRAM-MODL: mining enriched n-wise combinations of genomic features with Monte Carlo and dictionary learning

Quentin Ferré, Cécile Capponi, Denis Puthier
2021 NAR Genomics and Bioinformatics  
Most epigenetic marks, such as Transcriptional Regulators or histone marks, are biological objects known to work together in n-wise complexes. A suitable way to infer such functional associations between them is to study the overlaps of the corresponding genomic regions. However, the problem of the statistical significance of n-wise overlaps of genomic features is seldom tackled, which prevent rigorous studies of n-wise interactions. We introduce OLOGRAM-MODL, which considers overlaps between n
more » ... ≥ 2 sets of genomic regions, and computes their statistical mutual enrichment by Monte Carlo fitting of a Negative Binomial distribution, resulting in more resolutive P-values. An optional machine learning method is proposed to find complexes of interest, using a new itemset mining algorithm based on dictionary learning which is resistant to noise inherent to biological assays. The overall approach is implemented through an easy-to-use CLI interface for workflow integration, and a visual tree-based representation of the results suited for explicability. The viability of the method is experimentally studied using both artificial and biological data. This approach is accessible through the command line interface of the pygtftk toolkit, available on Bioconda and from
doi:10.1093/nargab/lqab114 pmid:34988437 pmcid:PMC8693575 fatcat:dljyvm6mrrarnfn7grom54g73m

IL-12 Signaling Contributes to the Reprogramming of Neonatal CD8+ T Cells

Darely Y. Gutiérrez-Reyna, Alejandra Cedillo-Baños, Linda A. Kempis-Calanis, Oscar Ramírez-Pliego, Lisa Bargier, Denis Puthier, Jose D. Abad-Flores, Morgane Thomas-Chollier, Denis Thieffry, Alejandra Medina-Rivera, Salvatore Spicuglia, Maria A. Santana
2020 Frontiers in Immunology  
Neonates are highly susceptible to intracellular pathogens, leading to high morbidity and mortality rates. CD8+ T lymphocytes are responsible for the elimination of infected cells. Understanding the response of these cells to normal and high stimulatory conditions is important to propose better treatments and vaccine formulations for neonates. We have previously shown that human neonatal CD8+ T cells overexpress innate inflammatory genes and have a low expression of cytotoxic and cell signaling
more » ... genes. To investigate the activation potential of these cells, we evaluated the transcriptome of human neonatal and adult naïve CD8+ T cells after TCR/CD28 signals ± IL-12. We found that in neonatal cells, IL-12 signals contribute to the adult-like expression of genes associated with cell-signaling, T-cell cytokines, metabolism, and cell division. Additionally, IL-12 signals contributed to the downregulation of the neutrophil signature transcription factor CEBPE and other immaturity related genes. To validate the transcriptome results, we evaluated the expression of a series of genes by RT-qPCR and the promoter methylation status on independent samples. We found that in agreement with the transcriptome, IL-12 signals contributed to the chromatin closure of neutrophil-like genes and the opening of cytotoxicity genes, suggesting that IL-12 signals contribute to the epigenetic reprogramming of neonatal lymphocytes. Furthermore, high expression of some inflammatory genes was observed in naïve and stimulated neonatal cells, in agreement with the high inflammatory profile of neonates to infections. Altogether our results point to an important contribution of IL-12 signals to the reprogramming of the neonatal CD8+ T cells.
doi:10.3389/fimmu.2020.01089 pmid:32582178 pmcid:PMC7292210 fatcat:wp6ogxpnwzhhflwkq6ka6hqyiq

A General Survey of Thymocyte Differentiation by Transcriptional Analysis of Knockout Mouse Models

Denis Puthier, Florence Joly, Magali Irla, Murielle Saade, Geneviève Victorero, Béatrice Loriod, Catherine Nguyen
2004 Journal of Immunology  
A General Survey of Thymocyte Differentiation by Transcriptional Analysis of Knockout Mouse Models 1 Denis Puthier, 2 Florence Joly, 2 Magali Irla, Murielle Saade, Geneviève Victorero, Béatrice Loriod  ... 
doi:10.4049/jimmunol.173.10.6109 pmid:15528347 fatcat:pl3snprg7vfwtazxqblxjmkofy

Drosophila Microbiota Modulates Host Metabolic Gene Expression via IMD/NF-κB Signaling

Berra Erkosar Combe, Arnaud Defaye, Noémie Bozonnet, Denis Puthier, Julien Royet, François Leulier, Eduardo Moreno
2014 PLoS ONE  
Citation: Combe BE, Defaye A, Bozonnet N, Puthier D, Royet J, et al. (2014) Drosophila Microbiota Modulates Host Metabolic Gene Expression via IMD/NF-kB Signaling. PLoS ONE 9(4): e94729.  ... 
doi:10.1371/journal.pone.0094729 pmid:24733183 pmcid:PMC3986221 fatcat:bdui6sl6v5gfrpbniahyhgvsiq

Genomic organization and the tissue distribution of alternatively spliced isoforms of the mouse Spatial gene

Magali Irla, Denis Puthier, Samuel Granjeaud, Murielle Saade, Geneviève Victorero, Marie-Geneviève Mattei, Catherine Nguyen
2004 BMC Genomics  
Denis Puthier is supported by an ANRS post-doctoral fellowship. Murielle Saade is supported by a grant from the INSERM région Provence-Alpes-Côte d'Azur.  ... 
doi:10.1186/1471-2164-5-41 pmid:15236666 pmcid:PMC481062 fatcat:zjy42pz25jh55ibtjrlfxtulve

An innovative approach to predict immune-associated genes mutually targeted by cow and human milk microRNAs expression profiles

Kaj Chokeshaiusaha, Thanida Sananmuang, Denis Puthier, Catherine Nguyen
2018 Veterinary World  
An innovative approach to predict immune-associated genes mutually targeted by cow and human milk microRNAs (miRNAs) expression profiles, Veterinary World, 11(9): 1203-1209. Abstract Aim: Milk is rich in miRNAs -the endogenous small non-coding RNA responsible for gene post-transcriptional silencing. Milk miRNAs were previously evidenced to affect consumer's immune response. While most studies relied on a few wellcharacterized milk miRNAs to relate their immunoregulatory roles on target genes
more » ... ng mammals, this study introduced a procedure to predict the target genes based on overall milk miRNA expression profiles -the miRNome data of cow and human. Materials and Methods: Cow and human milk miRNome expression datasets of cow and human milk lipids at 2, 4, and 6 months of lactation periods were preprocessed and predicted for their target genes using TargetScanHuman. Enrichment analysis was performed using target genes to extract the immune-associated gene ontology (GO) terms shared between the two species. The genes within these terms with more than 50 different miRNAs of each species targeting were selected and reviewed for their immunological functions. Results: A total of 146 and 129 miRNAs were identified in cow and human milk with several miRNAs reproduced from other previous reports. Enrichment analysis revealed nine immune-related GO terms shared between cow and human (adjusted p≤0.01). There were 14 genes related to these terms with more than 50 miRNA genes of each species targeting them. These genes were evidenced for their major roles in lymphocyte stimulation and differentiation. Conclusion: A novel procedure to determine mutual immune-associated genes targeted by milk miRNAs was demonstrated using cow and human milk miRNome data. As far as we know, this was the 1 st time that milk miRNA target genes had been identified based on such cross-species approach. Hopefully, the introduced strategy should hereby facilitate a variety of cross-species miRNA studies in the future.
doi:10.14202/vetworld.2018.1203-1209 pmid:30410222 pmcid:PMC6200572 fatcat:xtl4rb6owrffddgn2pvbkjckme

A comprehensive catalog of LncRNAs expressed in T-cell acute lymphoblastic leukemia

Yasmina Kermezli, Wiam Saadi, Mohamed Belhocine, Eve-Lyne Mathieu, Marc-Antoine Garibal, Vahid Asnafi, Mourad Aribi, Salvatore Spicuglia, Denis Puthier
2019 Leukemia and Lymphoma  
Several studies have demonstrated that LncRNAs can play major roles in cancer development. The creation of a catalog of LncRNAs expressed in T cell acute lymphoblastic leukemia (T-ALL) is thus of particular importance. However, this task is challenging as LncRNA expression is highly restricted in time and space manner and thus may greatly differ between samples. We performed a systematic transcript discovery in RNA-Seq data obtained from T-ALL primary cells and cell lines. This led to the
more » ... fication of 2560 novel LncRNAs. After the integration of these transcripts into a large compendium of LncRNAs (n = 30478) containing both known LncRNAs and those previously described in T-ALLs, we then performed a systematic genomic and epigenetic characterization of these transcript models demonstrating that these novel LncRNAs share properties with known LncRNAs. Finally, we provide evidence that these novel transcripts could be enriched in LncRNAs with potential oncogenic effects and identified a subset of LncRNAs coregulated with T-ALL oncogenes. Overall, our study represents a comprehensive resource of LncRNAs expressed in T-ALL and might provide new cues on the role of lncRNAs in this type of leukemia.
doi:10.1080/10428194.2018.1551534 pmid:30648438 fatcat:63mcdddbejd5hdbzf6wlgbjssq

Differential DNA methylation analysis across the promoter regions using methylated DNA immunoprecipitation sequencing profiling of porcine loin muscle

Kaj Chokeshaiusaha, Denis Puthier, Thanida Sananmuang, Em-on Olanratmanee, Catherine Nguyen, Roongtham Kedkovid
2020 Veterinary World  
and Aim: Pork leanness and marbling are among the essential traits of consumer preference. To acquire knowledge about universal epigenetic regulations for improving breed selection, a meta-analysis of methylated DNA immunoprecipitation sequencing (MeDIP-seq) profiling data of mixed loin muscle types was performed in this study. Materials and Methods: MeDIP-seq profiling datasets of longissimus dorsi muscle and psoas major muscles from male and female pigs of Landrace and Tibetan breeds were
more » ... rocessed and aligned to the porcine genome. Analysis of differential methylated DNA regions (DMRs) between the breeds was performed by focusing on transcription start sites (TSSs) of known genes (–20,000-3000 bases from TSS). All associated genes were further reviewed for their functions and predicted for transcription factors (TF) possibly associated with their TSSs. Results: When the methylation levels of DMRs in TSS regions of Landrace breed were compared to those of Tibetan breed, 10 DMRs were hypomethylated (Landrace < Tibetan), and 19 DMRs were hypermethylated (Landrace > Tibetan), accordingly (p≤0.001). According to the reviews about gene functions, all associated genes were pieces of evidence for their roles in a variety of muscle and lipid metabolisms. Prediction of the binding TFs revealed the six most abundant binding TFs to such DMRs-associated TSS (p≤0.0001) as follows: ZNF384, Foxd3, IRF1, KLF9, EWSR1-FLI1, HES5, and TFAP2A. Conclusion: Common DMRs-associated TSS between the lean-type and the marbled-type loin muscles were identified in this study. Interestingly, the genes associated with such regions were strongly evidenced for their possible roles on the muscle trait characteristics by which further novel research topics could be focused on them in the future.
doi:10.14202/vetworld.2020.1113-1125 pmid:32801562 pmcid:PMC7396332 fatcat:m424xi4oo5fvnja55hlllatzbi

Gene‐Expression Profiling Discriminates between Cerebral Malaria (CM)–Susceptible Mice and CM‐Resistant Mice

Nicolas F. Delahaye, Nicolas Coltel, Denis Puthier, Laurence Flori, Rémi Houlgatte, Fuad A. Iraqi, Catherine Nguyen, Georges E. Grau, Pascal Rihet
2006 Journal of Infectious Diseases  
The development of mouse cerebral malaria (CM) upon Plasmodium berghei ANKA infection is under genetic control. Brain gene expression patterns were investigated in well-defined genetically CM-resistant (BALB/c and DBA/2) and CM-susceptible (C57BL/6 and CBA/J) mouse strains by using cDNA microarrays. By combining transcriptional profiling with rigorous statistical methods and cluster analysis, we identified a set of 69 genes that perfectly discriminated between mouse strains and between
more » ... ant and CM-susceptible mice. The analysis of Gene Ontology terms revealed that the genes clustered and related to susceptibility to CM preferentially belonged to some biological process classes, such as those pertaining to immune responses. Using a false discovery rate of 5% and Welch t-test, we identified 31 genes with consistent differential expression between CM-resistant and CM-susceptible mice. These data indicate that microarray analysis may be useful to identify candidate genes potentially responsible for resistance or susceptibility to CM. Mouse Strains and Phenotyping Six to 8 weeks old BALB/c, DBA/2 (CM-R strains), C57BL/6 and CBA/J (CM-S strains) female, were obtained from IFFA CREDO (Ch. River Lab, France) and kept in our facilities. Five from each strain were infected by i.p. injection of P. berghei ANKA. Parasitemia was monitored daily on blood smear. The CM-S mice developed a neurological syndrome which occurred 6 to 7 days after parasite inoculation with a cumulative mortality of 100 %. The CM-R mice die during the 3 rd or the 4 th week of infection, with severe anaemia and hyperparasitemia [7] . Organ Sampling and Histology Brains were taken from CM-R and CM-S mice when the CM-S mice develop CM. Brains were completely removed and cut in two parts: one part was frozen in RNALater (Qiagen, TM) until RNA analysis, and the other one was embedded in Tissue Tek (Leica), snap frozen in liquid nitrogen and kept at -80°C until histopathological examination of cryosections. Histology consisted in specific antibody immunohistochemistry for VCAM-1 (Clone 429, BD Pharmingen) and ISCBP1 (C19, TEBU Bio). Afterwards, slides were photographed and protein expression was quantified using LUCIA software (Nikon) [8] . RNA Isolation and cDNA Microarray Hybridizations Total RNA from brains was extracted using TRIzol reagent (Gibco-BRL, Life Technologies). The quality of RNA was confirmed on a formaldehyde agarose gel, and the concentration of RNA was determined by reading absorbance at 260/280 nm. Each mRNA sample extracted from an individual sample was run on a single microarray. All microarray procedures were done at our microarray core facility ( cDNA microarrays were designed and HAL author manuscript inserm-00276272, version 1 NOTE. The genes, the expression of which significantly differed between CM-R and CM-S mice, are shown in bold. A false discovery rate (FDR) of 5% was used. a Group A: the expression of the gene differed between C57BL/6 and CBA/J mice. Group B: the expression of the gene differed between BALB/c and DBA/2 mice. Group C: the expression of the gene differed between C57BL/6 and CBA/J mice, and between BALB/c and DBA/2 mice. b Positive score: CM-S mice gene expression was higher than CM-R mice gene expression. Negative Score: CM-R mice gene expression was higher than CM-S mice gene expression. c Significant results with a FDR of 5% are indicated by an asterisk. d Results are shown for this clone. Similar results were obtained for the other clone.
doi:10.1086/498579 pmid:16362897 fatcat:jrmrikh4v5gxfexq6bjbno3rhq

A demonstration of the H3 trimethylation ChIP-seq analysis of galline follicular mesenchymal cells and male germ cells

Kaj Chokeshaiusaha, Denis Puthier, Catherine Nguyen, Thanida Sananmuang
2018 Asian-Australasian Journal of Animal Sciences  
Objective: Trimethylation of histone 3 (H3) at 4th lysine N-termini (H3K4me3) in gene promoter region was the universal marker of active genes specific to cell lineage. On the contrary, coexistence of trimethylation at 27th lysine (H3K27me3) in the same loci-the bivalent H3K4m3/H3K27me3 was known to suspend the gene transcription in germ cells, and could also be inherited to the developed stem cell. In galline species, throughout example of H3K4m3 and H3K27me3 ChIP-seq analysis was still not
more » ... vided. We therefore designed and demonstrated such procedures using ChIP-seq and mRNA-seq data of chicken follicular mesenchymal cells and male germ cells. Methods: Analytical workflow was designed and provided in this study. ChIP-seq and RNAseq datasets of follicular mesenchymal cells and male germ cells were acquired and properly preprocessed. Peak calling by Model-based analysis of ChIP-seq 2 was performed to identify H3K4m3 or H3K27me3 enriched regions (Fold-change≥2, FDR≤0.01) in gene promoter regions. Integrative genomics viewer was utilized for cellular retinoic acid binding protein 1 (CRABP1), growth differentiation factor 10 (GDF10), and gremlin 1 (GREM1) gene explorations. Results: The acquired results indicated that follicular mesenchymal cells and germ cells shared several unique gene promoter regions enriched with H3K4me3 (5,704 peaks) and also unique regions of bivalent H3K4m3/H3K27me3 shared between all cell types and germ cells (1,909 peaks). Subsequent observation of follicular mesenchyme-specific genes-CRABP1, GDF10, and GREM1 correctly revealed vigorous transcriptions of these genes in follicular mesenchymal cells. As expected, bivalent H3K4m3/H3K27me3 pattern was manifested in gene promoter regions of germ cells, and thus suspended their transcriptions. Conclusion: According the results, an example of chicken H3K4m3/H3K27me3 ChIP-seq data analysis was successfully demonstrated in this study. Hopefully, the provided methodology should hereby be useful for galline ChIP-seq data analysis in the future.
doi:10.5713/ajas.17.0744 pmid:29381903 pmcid:PMC5933975 fatcat:g2akrqm4greclhqrim4rwy74wu

ATAD2 controls chromatin-bound HIRA turnover

Tao Wang, Daniel Perazza, Fayçal Boussouar, Matteo Cattaneo, Alexandre Bougdour, Florent Chuffart, Sophie Barral, Alexandra Vargas, Ariadni Liakopoulou, Denis Puthier, Lisa Bargier, Yuichi Morozumi (+6 others)
2021 Life Science Alliance  
Taking advantage of the evolutionary conserved nature of ATAD2, we report here a series of parallel functional studies in human, mouse, and Schizosaccharomyces pombe to investigate ATAD2's conserved functions. In S. pombe, the deletion of ATAD2 ortholog, abo1, leads to a dramatic decrease in cell growth, with the appearance of suppressor clones recovering normal growth. The identification of the corresponding suppressor mutations revealed a strong genetic interaction between Abo1 and the
more » ... chaperone HIRA. In human cancer cell lines and in mouse embryonic stem cells, we observed that the KO of ATAD2 leads to an accumulation of HIRA. A ChIP-seq mapping of nucleosome-bound HIRA and FACT in Atad2 KO mouse ES cells demonstrated that both chaperones are trapped on nucleosomes at the transcription start sites of active genes, resulting in the abnormal presence of a chaperone-bound nucleosome on the TSS-associated nucleosome-free regions. Overall, these data highlight an important layer of regulation of chromatin dynamics ensuring the turnover of histone-bound chaperones.
doi:10.26508/lsa.202101151 pmid:34580178 pmcid:PMC8500222 fatcat:i3qwbcptancjnhfww4qnqi5q2m
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