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1. A longitudinal investigation of psychological distress in children during COVID-19: the role of socio-emotional vulnerability

Author

Catherine Raymond, Jessie Provencher, Alexe Bilodeau-Houle, Julie Leclerc, and Marie-France Marin

Subjects
covid-19, youth, anxiety, post-traumatic stress, depression, socio-emotional vulnerability, Psychiatry, RC435-571
Abstract

Background Although the COVID-19 pandemic has increased the incidence of distress in youth, some children show increased resilience, emphasizing the need to better understand the predictors of distress in youth. Objective This longitudinal study aimed to assess the combined impact of known socio-emotional predictors of stress-related psychopathology, namely anxiety sensitivity, anxiety trait, intolerance to uncertainty, and rumination, on COVID-related distress in healthy youth. Method A total of 92 parent-child dyads that previously participated in a laboratory-based experiment assessing observational fear learning in families between 2017 and 2019 (T0) were recontacted. Of them, 84 children aged between 9 and 14 agreed to participate. They completed online questionnaires in June 2020 (T1), September 2020 (T2), December 2020 (T3), and March 2021 (T4). Participants were free of mental illness at T0 and T1. To create a socio-emotional composite score (SECS), we measured anxiety sensitivity (Childhood Anxiety Sensitivity Index) at T0, trait anxiety (Trait subscale of the State-Trait Anxiety Inventory for Children (STAI-C)), intolerance to uncertainty (Intolerance of Uncertainty Scale for Children), and trait rumination (Children’s Response Style Scale) at T1 and created a weighted z-score. To assess symptoms of anxiety, post-traumatic stress (PTS), and depression in reaction to COVID-19, participants completed the State subscale of the STAI-C, the Children’s Revised Impact of Event Scale, and the Children’s Depression Inventory at T1–T4. Three general linear models were run with sex, age group (9–11 and 12+ years old), and SECS as predictors. Results Analyses revealed a SECS*Time interaction, with higher SECS predicting elevated anxiety symptoms at T1 and T4, and elevated PTS symptoms at T1 and T2. Conclusion These results suggest that healthy youth endorsing high levels of socio-emotional vulnerability to psychopathology have a higher risk of suffering from anxiety and PTS, but not depressive symptoms, in the year following a major stressor.

Published
2022
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2. Genetic predisposition to neural crest-derived tumors: revisiting the role of KIF1B

Author

Catherine Cardot Bauters, Emmanuelle Leteurtre, Bruno Carnaille, Christine Do Cao, Stéphanie Espiard, Malo Penven, Evelyne Destailleur, Isabelle Szuster, Tonio Lovecchio, Julie Leclerc, Fredéric Frénois, Emmanuel Esquivel, Patricia L M Dahia, Emilie Ait-Yahya, Michel Crépin, and Pascal Pigny

Subjects
endocrine tumor, genetic predisposition, pheochromocytoma, neural crest, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Objective: We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband’s brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis. Design and methods: Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations. Results: A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband’s brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected gran dfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband. Conclusion: In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.

Published
2020
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3. DiNAMO: highly sensitive DNA motif discovery in high-throughput sequencing data

Author

Chadi Saad, Laurent Noé, Hugues Richard, Julie Leclerc, Marie-Pierre Buisine, Hélène Touzet, and Martin Figeac

Subjects
Motif, DNA, Chip-Seq, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Discovering over-represented approximate motifs in DNA sequences is an essential part of bioinformatics. This topic has been studied extensively because of the increasing number of potential applications. However, it remains a difficult challenge, especially with the huge quantity of data generated by high throughput sequencing technologies. To overcome this problem, existing tools use greedy algorithms and probabilistic approaches to find motifs in reasonable time. Nevertheless these approaches lack sensitivity and have difficulties coping with rare and subtle motifs. Results We developed DiNAMO (for DNA MOtif), a new software based on an exhaustive and efficient algorithm for IUPAC motif discovery. We evaluated DiNAMO on synthetic and real datasets with two different applications, namely ChIP-seq peaks and Systematic Sequencing Error analysis. DiNAMO proves to compare favorably with other existing methods and is robust to noise. Conclusions We shown that DiNAMO software can serve as a tool to search for degenerate motifs in an exact manner using IUPAC models. DiNAMO can be used in scanning mode with sliding windows or in fixed position mode, which makes it suitable for numerous potential applications. Availability https://github.com/bonsai-team/DiNAMO.

Published
2018
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4. High cyclin E staining index in blastemal, stromal or epithelial cells is correlated with tumor aggressiveness in patients with nephroblastoma.

Author

Dominique Berrebi, Julie Leclerc, Gudrun Schleiermacher, Isabelle Zaccaria, Liliane Boccon-Gibod, Monique Fabre, Francis Jaubert, Alaa El Ghoneimi, Cécile Jeanpierre, and Michel Peuchmaur

Subjects
Medicine, Science
Abstract

PURPOSE: Identifying among nephroblastoma those with a high propensity for distant metastases using cell cycle markers: cyclin E as a regulator of progression through the cell cycle and Ki-67 as a tumor proliferation marker, since both are often deregulated in many human malignancies. METHODOLOGY/PRINCIPAL FINDINGS: A staining index (SI) was obtained by immunohistochemistry using anti-cyclin E and anti-Ki-67 antibodies in paraffin sections of 54 postchemotherapy nephroblastoma including 42 nephroblastoma without metastasis and 12 with metastases. Median cyclin E and Ki-67 SI were 46% and 33% in blastemal cells, 30% and 10% in stromal cells, 37% and 29.5% in epithelial cells. The highest values were found for anaplastic nephroblastoma. A correlation between cyclin E and Ki-67 SI was found for the blastemal component and for the epithelial component. Univariate analysis showed prognostic significance for metastases with cyclin E SI in stromal cells, epithelial cells and blastemal cells (p = 0.03, p = 0.01 and p = 0.002, respectively) as well as with Ki-67 SI in blastema (p

Published
2008
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5. Genetic predisposition to neural crest-derived tumors: revisiting the role of KIF1B

Author

Emmanuelle Leteurtre, Frédéric Frenois, Malo Penven, Evelyne Destailleur, Bruno Carnaille, Catherine Bauters, Emilie Ait-Yahya, Patricia L. M. Dahia, Christine Do Cao, Michel Crépin, Stéphanie Espiard, Pascal Pigny, Julie Leclerc, Isabelle Szuster, Emmanuel Esquivel, and Tonio Lovecchio

Subjects
0301 basic medicine, Proband, Endocrinology, Diabetes and Metabolism, endocrine tumor, 030105 genetics & heredity, Genetic analysis, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Germline, 03 medical and health sciences, symbols.namesake, Endocrinology, Internal Medicine, Genetic predisposition, Medicine, Multiplex ligation-dependent probe amplification, Allele, Exome sequencing, Sanger sequencing, Genetics, lcsh:RC648-665, business.industry, Research, pheochromocytoma, 030104 developmental biology, symbols, business, genetic predisposition, neural crest
Abstract

Objective We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband’s brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis. Design and methods Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations. Results A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband’s brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband. Conclusion In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.

Published
2020

6. Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome

Author

Cedrick Lefol, Gaëlle Bougeard, Julie Leclerc, Thierry Frebourg, Marie Pierre Buisine, Sylviane Olschwang, Kévin Cassinari, Qing Wang, Stéphanie Baert-Desurmont, Pierre Naïbo, Denis Boidin, Stéphanie Vasseur, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut Curie [Paris], Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Biologie et Physiopathologie des Cellules Mucipares (u377), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Neurosciences & Cognition - U 1172 (LilNCog), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Oncology, Amsterdam criteria, medicine.medical_specialty, [SDV]Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, PMS2, Medicine, Family history, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Haplotype, Microsatellite instability, medicine.disease, Penetrance, Lynch syndrome, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, business, Founder effect
Abstract

BackgroundHeterozygous germline PMS2 variants are responsible for about 5% of Lynch syndrome (LS) but their prevalence is most likely underestimated because of complicated routine screening caused by highly homologous pseudogenes. Consequently, there is limited knowledge on the implication of the PMS2 gene in LS.MethodsWe report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5.ResultsGenomic rearrangements account for 18% of alterations. The c.137G>T variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours from PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis.ConclusionOur results provide further insight into the role of the PMS2 gene in LS. While PMS2 variants are mostly detected in families not fulfilling Amsterdam criteria, which supports their lower penetrance, they can nevertheless cause early-onset cancers, highlighting the variability of their penetrance.

Published
2020
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7. Optimization of Next-Generation Sequencing Technologies for von Hippel Lindau (VHL) Mosaic Mutation Detection and Development of Confirmation Methods

Author

Catherine Cardot-Bauters, Michel Crépin, Pascal Plouvier, Pascal Pigny, Stéphane Richard, Emilie Ait Yahya, Brigitte Bressac-de Paillerets, Lucie Coppin, Sophie Lejeune, Anne-Sophie Jourdain, Julie Leclerc, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Immunologie intégrative des tumeurs (UMR 1186), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille

Subjects
Adult, Male, 0301 basic medicine, Adolescent, endocrine system diseases, Tumor suppressor gene, [SDV]Life Sciences [q-bio], Mutant, Biology, urologic and male genital diseases, DNA sequencing, Pathology and Forensic Medicine, 03 medical and health sciences, Exon, 0302 clinical medicine, Germline mutation, Limit of Detection, Humans, Digital polymerase chain reaction, Genetics, Mosaicism, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Middle Aged, Amplicon, Phenotype, female genital diseases and pregnancy complications, 3. Good health, 030104 developmental biology, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Mutation, Molecular Medicine, Plasmids
Abstract

Von Hippel-Lindau disease (VHL) is a monogenic disorder characterized by the development of tumors affecting the central nervous system, kidney, pancreas, or adrenal glands, and due to germline mutations in the VHL tumor suppressor gene. About 5% of patients with a typical VHL phenotype have no mutation detected by conventional techniques, so a postzygotic VHL mosaicism can be suspected. The aim of this study was therefore to implement a next-generation sequencing (NGS) strategy for VHL mosaic mutation detection, including an optimization of the original Personal Genome Machine design by enrichment with oligonucleotides corresponding to amplicons with insufficient depth of coverage. Two complementary strategies were developed for the confirmation of mosaic mutations identified by NGS, SNaPshot for variants present at an allelic ratio greater than 5%, and droplet digital PCR for allelic ratio above 1%. VHL mutant plasmids were generated to assess VHL mosaic mutation detection in different exons and to set up an internal quality control that could be included in each run or regularly to validate the assay. This strategy was applied to 47 patients with a suggestive or clinical VHL disease, and mosaic mutations were identified in 8.5% of patients. In conclusion, NGS technologies combined with SNaPshot or droplet digital PCR allow the detection and confirmation of mosaic mutations in a clinical laboratory setting.

Published
2019
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8. A multi‐level approach reveals key physiological and molecular traits in the response of two rice genotypes subjected to water deficit at the reproductive stage

Author

Bénédicte Favreau, Camille Gaal, Isabela Pereira de Lima, Gaétan Droc, Sandrine Roques, Armel Sotillo, Florence Guérard, Valérie Cantonny, Bertrand Gakière, Julie Leclercq, Tanguy Lafarge, and Marcel deRaissac

Subjects
development, gene networks, rice, transcriptomics, water deficit, Environmental sciences, GE1-350, Botany, QK1-989
Abstract

Abstract Rice is more vulnerable to drought than maize, wheat, and sorghum because its water requirements remain high throughout the rice life cycle. The effects of drought vary depending on the timing, intensity, and duration of the events, as well as on the rice genotype and developmental stage. It can affect all levels of organization, from genes to the cells, tissues, and/or organs. In this study, a moderate water deficit was applied to two contrasting rice genotypes, IAC 25 and CIRAD 409, during their reproductive stage. Multi‐level transcriptomic, metabolomic, physiological, and morphological analyses were performed to investigate the complex traits involved in their response to drought. Weighted gene network correlation analysis was used to identify the specific molecular mechanisms regulated by each genotype, and the correlations between gene networks and phenotypic traits. A holistic analysis of all the data provided a deeper understanding of the specific mechanisms regulated by each genotype, and enabled the identification of gene markers. Under non‐limiting water conditions, CIRAD 409 had a denser shoot, but shoot growth was slower despite better photosynthetic performance. Under water deficit, CIRAD 409 was weakly affected regardless of the plant level analyzed. In contrast, IAC 25 had reduced growth and reproductive development. It regulated transcriptomic and metabolic activities at a high level, and activated a complex gene regulatory network involved in growth‐limiting processes. By comparing two contrasting genotypes, the present study identified the regulation of some fundamental processes and gene markers, that drive rice development, and influence its response to water deficit, in particular, the importance of the biosynthetic and regulatory pathways for cell wall metabolism. These key processes determine the biological and mechanical properties of the cell wall and thus influence plant development, organ expansion, and turgor maintenance under water deficit. Our results also question the genericity of the antagonism between morphogenesis and organogenesis observed in the two genotypes.

Published
2023
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9. Colon cancer stemness as a reversible epigenetic state: Implications for anticancer therapies

Author

Aïcha Ouelkdite-Oumouchal, Julie Leclerc, Audrey Vincent, Bernadette Neve, Isabelle Van Seuningen, Mouloud Souidi, Jonckheere, Nicolas, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Laboratoire de Biochimie et Biologie Moléculaire [CHRU Lille] (Pôle de Biologie Pathologie Génétique), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 'Institut National de la Santé et de la Recherche Médicale', (Inserm), 'Centre National de la Recherche Scientifique' (CNRS), 'la Ligue Nationale contre le Cancer' (Committees 59, 60 and 62)., Laboratoire d'Études Rurales (LER), Université Lumière - Lyon 2 (UL2), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Laboratoire Epigenetique et Cancer, Centre National de la Recherche Scientifique (CNRS), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Laboratoire Epigénétique et Cancer (LEC), Département Biologie des Génomes (DBG), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Histology, Colorectal cancer, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer stem cell, Genetics, medicine, Chromatin modifying enzymes, Epigenetics, CD133, CD44, Molecular Biology, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, biology, Cluster of differentiation, Cancer stem cells, Cancer, Cell Biology, medicine.disease, 3. Good health, Colon cancer, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Cancer research, Histone deacetylase, CD166
Abstract

International audience; The recent discovery of cancer cell plasticity, i.e. their ability to reprogram into cancer stem cells (CSCs) either naturally or under chemotherapy and/or radiotherapy, has changed, once again, the way we consider cancer treatment. If cancer stemness is a reversible epigenetic state rather than a genetic identity, opportunities will arise for therapeutic strategies that remodel epigenetic landscapes of CSCs. However, the systematic use of DNA methyltransferase and histone deacetylase inhibitors, alone or in combination, in advanced solid tumors including colorectal cancers, regardless of their molecular subtypes, does not seem to be the best strategy. In this review, we first summarize the knowledge researchers have gathered on the epigenetic signatures of CSCs with the difficulty of isolating rare populations of cells. We raise questions about the relevant use of currently available epigenetic inhibitors (epidrugs) while the expression of numerous cancer stem cell markers are often repressed by epigenetic mechanisms. These markers include the three cluster of differentiation CD133, CD44 and CD166 that have been extensively used for the isolation of colon CSCs.and . Finally, we describe current treatment strategies using epidrugs, and we hypothesize that, using correlation tools comparing associations of relevant CSC markers with chromatin modifier expression, we could identify better candidates for epienzyme targeting.

Published
2019
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10. Messenger RNA Life-Cycle in Cancer Cells: Emerging Role of Conventional and Non-Conventional RNA-Binding Proteins?

Author

Lucie Coppin, Julie Leclerc, Audrey Vincent, Nicole Porchet, Pascal Pigny, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and VINCENT, AUDREY

Subjects
mRNA life-cycle, mRNA-binding domains, Transcription, Genetic, intrinsically disordered regions, RNA Splicing, RNA Stability, Review, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], cytoplasmic RNA granules, RNA Transport, lcsh:Chemistry, mRNA fate, Neoplasms, DNA and RNA-binding proteins, galectin-3, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], mRNA-binding proteins, Animals, Humans, Protein Interaction Domains and Motifs, RNA regulon, Molecular Targeted Therapy, RNA, Messenger, RNA Processing, Post-Transcriptional, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, RNA-Binding Proteins, low complexity disordered regions, Gene Expression Regulation, Neoplastic, lcsh:Biology (General), lcsh:QD1-999, Protein Binding
Abstract

Functional specialization of cells and tissues in metazoans require specific gene expression patterns. Biological processes, thus, need precise temporal and spatial coordination of gene activity. Regulation of the fate of messenger RNA plays a crucial role in this context. In the present review, the current knowledge related to the role of RNA-binding proteins in the whole mRNA life-cycle is summarized. This field opens up a new angle for understanding the importance of the post-transcriptional control of gene expression in cancer cells. The emerging role of non-classic RNA-binding proteins is highlighted. The goal of this review is to encourage readers to view, through the mRNA life-cycle, novel aspects of the molecular basis of cancer and the potential to develop RNA-based therapies.

Published
2018
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11. DiNAMO: Exact method for degenerate IUPAC motifs discovery, characterization of sequence-specific errors

Author

Chadi Saad, Laurent Noé, Hugues Richard, Julie Leclerc, Marie-Pierre Buisine, Helene Touzet, Martin Figeac, Bioinformatics and Sequence Analysis (BONSAI), Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Touzet, Helene

Subjects
[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract

National audience; Next generation sequencing technologies are still associated with relatively high error rates, about 1%, which correspond to thousands of errors in the scale of a complete genome. Each region needs therefore to be sequenced several times and variants are usually filtered based on depth criteria. The significant number of artifacts, in spite of those filters, shows the limit of conventional approaches and indicates that some sequencing artifacts are recurrent. This recurrence underlines that sequencing errors can depend on the upstream nucleotide sequence context. Our goal is to search for overrepresented motifs that tend to induce sequencing errors. Previous studies showed that some motifs, such as GGT [1,2], induce sequencing errors in the Illumina technologies. However, these studies were dedicated to exact motifs, and did not take into account approximate motifs, limiting the statistical power of such approaches. On the other hand, some tools, such as FIRE [3], DREME [4] and Discrover [5], were developed to search for degenerate motifs over the 15-letter IUPAC alphabet in the context of chip-seq studies. However, these tools use greedy algorithms, implying a lack of sensitivity. So we developed an exact algorithm to search for degenerate motifs by enumerating all possible IUPAC motifs. This algorithm is based on mutual information and uses hashtables with graphs data structure to store the motifs. It is independent from the sequencing technology. Experimental results on real data show that there are many overrepresented motifs upstream of sequencing artifacts. These latter are identified through the strand bias between forward and reverse reads. The homopoly-mer of length 3 CCC seems to be sufficient to induce errors on IonTorrent. On Illumina, motifs are mainly composed of GGC followed by GGT (like: TGGCNGGT) or homopolymers. We have also noticed a base quality fall after the detected motifs. Our exact algorithm requires less than one minute (Intel R Core TM i5-4570 CPU, 3.20GHz), and less than 2GB of RAM to search for full degenerate motifs of length 6 on a dataset of approximately 24000 sequences, extracted from 11 exomes sequenced on IonTorrent Proton.

Published
2017

18. CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders

Author

Christel, Thauvin-Robinet, Anne, Munck, Frédéric, Huet, Alix, de Becdelièvre, Clément, Jimenez, Guy, Lalau, Elodie, Gautier, Jacques, Rollet, Jean, Flori, Raphaëlle, Nové-Josserand, Jean-Claude, Soufir, Alain, Haloun, Dominique, Hubert, Elise, Houssin, Gil, Bellis, Gilles, Rault, Albert, David, Laurent, Janny, Raphaël, Chiron, Nathalie, Rives, Dominique, Hairion, Patrick, Collignon, Antoine, Valeri, Gilles, Karsenty, Annick, Rossi, Marie-Pierre, Audrézet, Claude, Férec, Julie, Leclerc, Marie des, Georges, Mireille, Claustres, Thierry, Bienvenu, Bénédicte, Gérard, Pierre, Boisseau, Faïza, Cabet-Bey, David, Cheillan, Delphine, Feldmann, Christine, Clavel, Eric, Bieth, Albert, Iron, Brigitte, Simon-Bouy, Vincent, Izard, Julie, Steffann, Stéphane, Viville, Catherine, Costa, Véronique, Drouineaud, Patricia, Fauque, Christine, Binquet, Claire, Bonithon-Kopp, Mike A, Morris, Laurence, Faivre, Michel, Goossens, Michel, Roussey, Emmanuelle, Girodon, L, Weiss, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de pédiatrie (CHU de Dijon), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), CIC Cochin Pasteur (CIC 1417), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe hospitalier Broca-Université Paris Descartes - Paris 5 (UPD5)-Hôtel-Dieu-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut national d'études démographiques (INED), Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Centre de Perharidy-Cellule de Coordination du Réseau Mucoviscidose (CECOREM), MLab, Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), CHRU de Brest, service de chirurgie urologique et de la transplantation reinale (CHU - BREST - Urologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Chirurgie urologique et transplantation rénale [Hôpital de la Conception - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Service d'hématologie et immunologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service de génétique médicale [CHU Nantes], Service d'Endocrinologie Moléculaire et Maladies rares, Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plasticité de l'épithélium respiratoire dans les conditions normales et pathologiques - UMR-S 903 (PERPMP), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Reims Champagne-Ardenne (URCA), CHU Toulouse [Toulouse], Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Centre Hospitalier de Versailles André Mignot (CHV), Université Paris Descartes - Paris 5 (UPD5), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biologie de la reproduction CECOS - [CHU de Dijon], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de Pédiatrie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Gamétogenèse et Qualité du Gamète (GQG), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, Droit et Santé-Université de Lille, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service de biochimie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], and Centre Hospitalier de Versailles (CHV)

Subjects
Infertility, Male, medicine.medical_specialty, Heterozygote, Cystic Fibrosis, Offspring, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Gene mutation, Compound heterozygosity, Asymptomatic, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Vas Deferens, Male Urogenital Diseases, Mutation Rate, Internal medicine, Prenatal Diagnosis, Genotype, Genetics, medicine, Humans, Family history, Child, Sweat, Genetics (clinical), Infertility, Male, 030304 developmental biology, 0303 health sciences, business.industry, Infant, Newborn, Infant, medicine.disease, 3. Good health, Phenotype, 030228 respiratory system, Child, Preschool, Immunology, Mutation, Female, medicine.symptom, business
Abstract

International audience; BACKGROUND:The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma.METHODS:Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics.RESULTS:97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation.CONCLUSIONS:Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD

Published
2013
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19. p.Ser1235Arg should no longer be considered as a Cystic Fibrosis mutation: results from a large collaborative study: p.Ser1235Arg is not associated with CF disease

Author

Emmanuelle Girodon, Julie Leclerc, Faïza Cabet-Bey, Thierry Bienvenu, Albert Iron, Marie des Georges, Martine Blayau, Guy Lalau, Hervé Mittre, Delphine Feldmann, Mireille Claustres, Catherine Costa, Céline René, Damien Paulet, C. Guittard, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), INSERM U955, équipe 11, Service de Biochimie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Endocrinologie Moléculaire et Maladies rares, Hospices Civils de Lyon (HCL), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de biochimie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Models, Molecular, medicine.medical_specialty, Heterozygote, diagnosis, Genetic counseling, Population, Molecular Sequence Data, Mutation, Missense, Cystic Fibrosis Transmembrane Conductance Regulator, Prenatal diagnosis, Biology, Compound heterozygosity, Arginine, Cystic fibrosis, Gastroenterology, Article, cystic fibrosis, 03 medical and health sciences, Vas Deferens, Male Urogenital Diseases, Pregnancy, Internal medicine, Prenatal Diagnosis, Genetics, medicine, Serine, Missense mutation, Humans, Amino Acid Sequence, education, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Molecular Epidemiology, genetic counseling, 030305 genetics & heredity, medicine.disease, Cystic fibrosis transmembrane conductance regulator, 3. Good health, Urogenital Abnormalities, Mutation (genetic algorithm), biology.protein, Female, mutation
Abstract

International audience; Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, initially reported in a CF patient with a second mutation (p.Gly628Arg) on the same allele, is a relatively frequent finding. To clarify its clinical significance, we collected data from 104 subjects heterozygous for the mutation p.Ser1235Arg from the French CF network, addressed for various indications including classical CF, atypical phenotypes or carrier screening in subjects with or without a family history. Among them, twenty-six patients (five having CF, ten CBAVD -Congenital Absence of the Vas Deferens- and eleven with CF-like symptoms) and fourteen healthy subjects were compound heterozygous for a second CFTR mutation. An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Moreover, epidemiological data from more than 2100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. These data, added to the fact that in silico analysis and functional assays suggest a benign nature of this substitution gives several lines of evidence against an association of p.Ser1235Arg with CF or CBAVD.

Published
2010
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20. An Epigenetic Alphabet of Crop Adaptation to Climate Change

Author

Francesco Guarino, Angela Cicatelli, Stefano Castiglione, Dolores R. Agius, Gul Ebru Orhun, Sotirios Fragkostefanakis, Julie Leclercq, Judit Dobránszki, Eirini Kaiserli, Michal Lieberman-Lazarovich, Merike Sõmera, Cecilia Sarmiento, Cristina Vettori, Donatella Paffetti, Anna M. G. Poma, Panagiotis N. Moschou, Mateo Gašparović, Sanaz Yousefi, Chiara Vergata, Margot M. J. Berger, Philippe Gallusci, Dragana Miladinović, and Federico Martinelli

Subjects
abiotic stresses, adaptation, climate change, epigenetics, environmental stresses, epigenetic code, Genetics, QH426-470
Abstract

Crop adaptation to climate change is in a part attributed to epigenetic mechanisms which are related to response to abiotic and biotic stresses. Although recent studies increased our knowledge on the nature of these mechanisms, epigenetics remains under-investigated and still poorly understood in many, especially non-model, plants, Epigenetic modifications are traditionally divided into two main groups, DNA methylation and histone modifications that lead to chromatin remodeling and the regulation of genome functioning. In this review, we outline the most recent and interesting findings on crop epigenetic responses to the environmental cues that are most relevant to climate change. In addition, we discuss a speculative point of view, in which we try to decipher the “epigenetic alphabet” that underlies crop adaptation mechanisms to climate change. The understanding of these mechanisms will pave the way to new strategies to design and implement the next generation of cultivars with a broad range of tolerance/resistance to stresses as well as balanced agronomic traits, with a limited loss of (epi)genetic variability.

Published
2022
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21. Post-transcriptional regulation of several biological processes involved in latex production in Hevea brasiliensis

Author

Julie Leclercq, Shuangyang Wu, Benoît Farinas, Stéphanie Pointet, Bénédicte Favreau, Hélène Vignes, Kuswanhadi Kuswanhadi, Enrique Ortega-Abboud, Jean-François Dufayard, Shenghan Gao, Gaëtan Droc, Songnian Hu, Chaorong Tang, and Pascal Montoro

Subjects
Small RNA, miRNA, Degradome, Rubber tree, Crop epigenomics, Abiotic stress, Medicine, Biology (General), QH301-705.5
Abstract

Background Small RNAs modulate plant gene expression at both the transcriptional and post-transcriptional level, mostly through the induction of either targeted DNA methylation or transcript cleavage, respectively. Small RNA networks are involved in specific plant developmental processes, in signaling pathways triggered by various abiotic stresses and in interactions between the plant and viral and non-viral pathogens. They are also involved in silencing maintenance of transposable elements and endogenous viral elements. Alteration in small RNA production in response to various environmental stresses can affect all the above-mentioned processes. In rubber trees, changes observed in small RNA populations in response to trees affected by tapping panel dryness, in comparison to healthy ones, suggest a shift from a transcriptional to a post-transcriptional regulatory pathway. This is the first attempt to characterise small RNAs involved in post-transcriptional silencing and their target transcripts in Hevea. Methods Genes producing microRNAs (MIR genes) and loci producing trans-activated small interfering RNA (ta-siRNA) were identified in the clone PB 260 re-sequenced genome. Degradome libraries were constructed with a pool of total RNA from six different Hevea tissues in stressed and non-stressed plants. The analysis of cleaved RNA data, associated with genomics and transcriptomics data, led to the identification of transcripts that are affected by 20–22 nt small RNA-mediated post-transcriptional regulation. A detailed analysis was carried out on gene families related to latex production and in response to growth regulators. Results Compared to other tissues, latex cells had a higher proportion of transcript cleavage activity mediated by miRNAs and ta-siRNAs. Post-transcriptional regulation was also observed at each step of the natural rubber biosynthesis pathway. Among the genes involved in the miRNA biogenesis pathway, our analyses showed that all of them are expressed in latex. Using phylogenetic analyses, we show that both the Argonaute and Dicer-like gene families recently underwent expansion. Overall, our study underlines the fact that important biological pathways, including hormonal signalling and rubber biosynthesis, are subject to post-transcriptional silencing in laticifers.

Published
2020
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22. The Identification of Small RNAs Differentially Expressed in Apple Buds Reveals a Potential Role of the Mir159-MYB Regulatory Module during Dormancy

Author

Julio Garighan, Etienne Dvorak, Joan Estevan, Karine Loridon, Bruno Huettel, Gautier Sarah, Isabelle Farrera, Julie Leclercq, Priscila Grynberg, Roberto Coiti Togawa, Marcos Mota do Carmo Costa, Evelyne Costes, and Fernando Andrés

Subjects
dormancy, apple tree, small RNAs, miR159, Botany, QK1-989
Abstract

Winter dormancy is an adaptative mechanism that temperate and boreal trees have developed to protect their meristems against low temperatures. In apple trees (Malus domestica), cold temperatures induce bud dormancy at the end of summer/beginning of the fall. Apple buds stay dormant during winter until they are exposed to a period of cold, after which they can resume growth (budbreak) and initiate flowering in response to warmer temperatures in spring. It is well-known that small RNAs modulate temperature responses in many plant species, but however, how small RNAs are involved in genetic networks of temperature-mediated dormancy control in fruit tree species remains unclear. Here, we have made use of a recently developed ARGONAUTE (AGO)-purification technique to isolate small RNAs from apple buds. A small RNA-seq experiment resulted in the identification of 17 micro RNAs (miRNAs) that change their pattern of expression in apple buds during dormancy. Furthermore, the functional analysis of their predicted target genes suggests a main role of the 17 miRNAs in phenylpropanoid biosynthesis, gene regulation, plant development and growth, and response to stimulus. Finally, we studied the conservation of the Arabidopsis thaliana regulatory miR159-MYB module in apple in the context of the plant hormone abscisic acid homeostasis.

Published
2021
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23. Ethylene Response Factors Are Controlled by Multiple Harvesting Stresses in Hevea brasiliensis.

Author

Riza-Arief Putranto, Cuifang Duan, Kuswanhadi, Tetty Chaidamsari, Maryannick Rio, Piyanuch Piyatrakul, Eva Herlinawati, Julien Pirrello, Florence Dessailly, Julie Leclercq, François Bonnot, Chaorong Tang, Songnian Hu, and Pascal Montoro

Subjects
Medicine, Science
Abstract

Tolerance of recurrent mechanical wounding and exogenous ethylene is a feature of the rubber tree. Latex harvesting involves tapping of the tree bark and ethephon is applied to increase latex flow. Ethylene is an essential element in controlling latex production. The ethylene signalling pathway leads to the activation of Ethylene Response Factor (ERF) transcription factors. This family has been identified in Hevea brasiliensis. This study set out to understand the regulation of ERF genes during latex harvesting in relation to abiotic stress and hormonal treatments. Analyses of the relative transcript abundance were carried out for 35 HbERF genes in latex, in bark from mature trees and in leaves from juvenile plants under multiple abiotic stresses. Twenty-one HbERF genes were regulated by harvesting stress in laticifers, revealing an overrepresentation of genes in group IX. Transcripts of three HbERF-IX genes from HbERF-IXc4, HbERF-IXc5 and HbERF-IXc6 were dramatically accumulated by combining wounding, methyl jasmonate and ethylene treatments. When an ethylene inhibitor was used, the transcript accumulation for these three genes was halted, showing ethylene-dependent induction. Subcellular localization and transactivation experiments confirmed that several members of HbERF-IX are activator-type transcription factors. This study suggested that latex harvesting induces mechanisms developed for the response to abiotic stress. These mechanisms probably depend on various hormonal signalling pathways. Several members of HbERF-IX could be essential integrators of complex hormonal signalling pathways in Hevea.

Published
2015
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24. Sequence and expression analyses of ethylene response factors highly expressed in latex cells from Hevea brasiliensis.

Author

Piyanuch Piyatrakul, Meng Yang, Riza-Arief Putranto, Julien Pirrello, Florence Dessailly, Songnian Hu, Marilyne Summo, Kannikar Theeravatanasuk, Julie Leclercq, Kuswanhadi, and Pascal Montoro

Subjects
Medicine, Science
Abstract

The AP2/ERF superfamily encodes transcription factors that play a key role in plant development and responses to abiotic and biotic stress. In Hevea brasiliensis, ERF genes have been identified by RNA sequencing. This study set out to validate the number of HbERF genes, and identify ERF genes involved in the regulation of latex cell metabolism. A comprehensive Hevea transcriptome was improved using additional RNA reads from reproductive tissues. Newly assembled contigs were annotated in the Gene Ontology database and were assigned to 3 main categories. The AP2/ERF superfamily is the third most represented compared with other transcription factor families. A comparison with genomic scaffolds led to an estimation of 114 AP2/ERF genes and 1 soloist in Hevea brasiliensis. Based on a phylogenetic analysis, functions were predicted for 26 HbERF genes. A relative transcript abundance analysis was performed by real-time RT-PCR in various tissues. Transcripts of ERFs from group I and VIII were very abundant in all tissues while those of group VII were highly accumulated in latex cells. Seven of the thirty-five ERF expression marker genes were highly expressed in latex. Subcellular localization and transactivation analyses suggested that HbERF-VII candidate genes encoded functional transcription factors.

Published
2014
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