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1. The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions

Author

Marine Lanfranchi, Sozerko Yandiev, Géraldine Meyer-Dilhet, Salma Ellouze, Martijn Kerkhofs, Raphael Dos Reis, Audrey Garcia, Camille Blondet, Alizée Amar, Anita Kneppers, Hélène Polvèche, Damien Plassard, Marc Foretz, Benoit Viollet, Kei Sakamoto, Rémi Mounier, Cyril F. Bourgeois, Olivier Raineteau, Evelyne Goillot, and Julien Courchet

Subjects
Science
Abstract

Abstract The cellular mechanisms underlying axonal morphogenesis are essential to the formation of functional neuronal networks. We previously identified the autism-linked kinase NUAK1 as a central regulator of axon branching through the control of mitochondria trafficking. However, (1) the relationship between mitochondrial position, function and axon branching and (2) the downstream effectors whereby NUAK1 regulates axon branching remain unknown. Here, we report that mitochondria recruitment to synaptic boutons supports collateral branches stabilization rather than formation in mouse cortical neurons. NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration, and upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Finally, we found that NUAK1 regulates axon branching through the mitochondria-targeted microprotein BRAWNIN. Our results demonstrate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondrial distribution and metabolic activity.

Published
2024
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2. Dysregulated expression of cholesterol biosynthetic genes in Alzheimer's disease alters epigenomic signatures of hippocampal neurons

Author

Isabel Paiva, Jonathan Seguin, Iris Grgurina, Akash Kumar Singh, Brigitte Cosquer, Damien Plassard, Laura Tzeplaeff, Stephanie Le Gras, Ludovica Cotellessa, Charles Decraene, Johanne Gambi, Rafael Alcala-Vida, Muthusamy Eswaramoorthy, Luc Buée, Jean-Christophe Cassel, Paolo Giacobini, David Blum, Karine Merienne, Tapas K. Kundu, and Anne-Laurence Boutillier

Subjects
Tauopathy, Aging, Epigenetics, Histone acetylation, Cholesterol, CSP-TTK21, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Aging is the main risk factor of cognitive neurodegenerative diseases such as Alzheimer's disease, with epigenome alterations as a contributing factor. Here, we compared transcriptomic/epigenomic changes in the hippocampus, modified by aging and by tauopathy, an AD-related feature. We show that the cholesterol biosynthesis pathway is severely impaired in hippocampal neurons of tauopathic but not of aged mice pointing to vulnerability of these neurons in the disease. At the epigenomic level, histone hyperacetylation was observed at neuronal enhancers associated with glutamatergic regulations only in the tauopathy. Lastly, a treatment of tau mice with the CSP-TTK21 epi-drug that restored expression of key cholesterol biosynthesis genes counteracted hyperacetylation at neuronal enhancers and restored object memory. As acetyl-CoA is the primary substrate of both pathways, these data suggest that the rate of the cholesterol biosynthesis in hippocampal neurons may trigger epigenetic-driven changes, that may compromise the functions of hippocampal neurons in pathological conditions.

Published
2024
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3. Analysis of the transcriptome of bovine endometrial cells isolated by laser micro-dissection (2): impacts of post-partum negative energy balance on stromal, glandular and luminal epithelial cells

Author

Wiruntita Chankeaw, Sandra Lignier, Christophe Richard, Theodoros Ntallaris, Mariam Raliou, Yongzhi Guo, Damien Plassard, Claudia Bevilacqua, Olivier Sandra, Göran Andersson, Patrice Humblot, and Gilles Charpigny

Subjects
Negative energy balance, Endometrium, Cell type-specific, Transcriptome, LCM, RNA-seq, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background In post-partum dairy cows, the energy needs to satisfy high milk production induces a status of more or less pronounced Negative Energy Balance (NEB). NEB associated with fat mobilization impairs reproductive function. In a companion paper, we described constitutive gene expression in the three main endometrial cell types (stromal, glandular and luminal epithelial cells) isolated by laser capture micro-dissection (LCM) showing the specificities of their transcriptomic profiles. This study investigates the specific impact of NEB on gene expression in these cells around 80 days after parturition at day 15 of the oestrus cycle and describes their specific response to NEB. Results Following the description of their constitutive expression, the transcriptome profiles obtained by RNA sequencing of the three cells types revealed that differences related to the severity of NEB altered mainly specific patterns of expression related to individual cell types. Number of differentially expressed genes between severe NEB (SNEB) and mild NEB (MNEB) cows was higher in ST than in LE and GE, respectively. SNEB was associated with differential expression of genes coding for proteins involved in metabolic processes and embryo-maternal interactions in ST. Under-expression of genes encoding proteins with functions related to cell structure was found in GE whereas genes encoding proteins participating in pro-inflammatory pathways were over-expressed. Genes associated to adaptive immunity were under-expressed in LE. Conclusion The severity of NEB after calving is associated with changes in gene expression around 80 days after parturition corresponding to the time of breeding. Specific alterations in GEs are associated with activation of pro-inflammatory mechanisms. Concomitantly, changes in the expression of genes encoding proteins involved in cell interactions and maternal recognition of pregnancy takes place in ST. The combination of these effects possibly altering the uterine environment and embryo maternal interactions may negatively influence the establishment of pregnancy.

Published
2021
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4. Analysis of the transcriptome of bovine endometrial cells isolated by laser micro-dissection (1): specific signatures of stromal, glandular and luminal epithelial cells

Author

Wiruntita Chankeaw, Sandra Lignier, Christophe Richard, Theodoros Ntallaris, Mariam Raliou, Yongzhi Guo, Damien Plassard, Claudia Bevilacqua, Olivier Sandra, Göran Andersson, Patrice Humblot, and Gilles Charpigny

Subjects
Cow, Endometrium, Cell type-specific, Transcriptome, LCM, RNA-seq, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background A number of studies have examined mRNA expression profiles of bovine endometrium at estrus and around the peri-implantation period of pregnancy. However, to date, these studies have been performed on the whole endometrium which is a complex tissue. Consequently, the knowledge of cell-specific gene expression, when analysis performed with whole endometrium, is still weak and obviously limits the relevance of the results of gene expression studies. Thus, the aim of this study was to characterize specific transcriptome of the three main cell-types of the bovine endometrium at day-15 of the estrus cycle. Results In the RNA-Seq analysis, the number of expressed genes detected over 10 transcripts per million was 6622, 7814 and 8242 for LE, GE and ST respectively. ST expressed exclusively 1236 genes while only 551 transcripts were specific to the GE and 330 specific to LE. For ST, over-represented biological processes included many regulation processes and response to stimulus, cell communication and cell adhesion, extracellular matrix organization as well as developmental process. For GE, cilium organization, cilium movement, protein localization to cilium and microtubule-based process were the only four main biological processes enriched. For LE, over-represented biological processes were enzyme linked receptor protein signaling pathway, cell-substrate adhesion and circulatory system process. Conclusion The data show that each endometrial cell-type has a distinct molecular signature and provide a significantly improved overview on the biological process supported by specific cell-types. The most interesting result is that stromal cells express more genes than the two epithelial types and are associated with a greater number of pathways and ontology terms.

Published
2021
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5. The related coactivator complexes SAGA and ATAC control embryonic stem cell self-renewal through acetyltransferase-independent mechanisms

Author

Veronique Fischer, Damien Plassard, Tao Ye, Bernardo Reina-San-Martin, Matthieu Stierle, Laszlo Tora, and Didier Devys

Subjects
mouse embryonic stem cells, coactivator complexes, SAGA, ATAC, Pol II transcription, 4sU labeling, Biology (General), QH301-705.5
Abstract

Summary: SAGA (Spt-Ada-Gcn5 acetyltransferase) and ATAC (Ada-two-A-containing) are two related coactivator complexes, sharing the same histone acetyltransferase (HAT) subunit. The HAT activities of SAGA and ATAC are required for metazoan development, but the role of these complexes in RNA polymerase II transcription is less understood. To determine whether SAGA and ATAC have redundant or specific functions, we compare the effects of HAT inactivation in each complex with that of inactivation of either SAGA or ATAC core subunits in mouse embryonic stem cells (ESCs). We show that core subunits of SAGA or ATAC are required for complex assembly and mouse ESC growth and self-renewal. Surprisingly, depletion of HAT module subunits causes a global decrease in histone H3K9 acetylation, but does not result in significant phenotypic or transcriptional defects. Thus, our results indicate that SAGA and ATAC are differentially required for self-renewal of mouse ESCs by regulating transcription through different pathways in a HAT-independent manner.

Published
2021
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6. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D. M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A. J. Tijssen, Arn M. J. M. van den Maagdenberg, and Christel Depienne

Subjects
Science
Abstract

Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.

Published
2019
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7. Supplementary Data from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Material and Methods, Figure legends

Published
2023
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8. Figure S5 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Phenotypic, transcriptomic and genetic validation of PDX models

Published
2023
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9. Supplementary Table 3 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

List of the SNVs identified through RNA-sequencing

Published
2023
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10. Supplementary Table 7 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Differentially expressed genes in the human B-ALL cohort

Published
2023
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11. Supplementary Table 1 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Characteristics of the B-ALL cohort

Published
2023
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12. Supplementary Table 8 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Reagents and Resources

Published
2023
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13. Data from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Purpose:Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL.Experimental Design:To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents.Results:Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine.Conclusions:Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.

Published
2023
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14. Supplementary Table 2 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

List of the SNVs identified through whole exome sequencing

Published
2023
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15. Supplementary Table 4 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

List of fusion transcripts identified through RNA-sequencing

Published
2023
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16. Supplementary Table 6 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

List of datasets enriched in murine B cell precursors (GSEA analyses)

Published
2023
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17. GnRH replacement rescues cognition in Down syndrome

Author

Maria Manfredi-Lozano, Valerie Leysen, Michela Adamo, Isabel Paiva, Renaud Rovera, Jean-Michel Pignat, Fatima Ezzahra Timzoura, Michael Candlish, Sabiha Eddarkaoui, Samuel A. Malone, Mauro S. B. Silva, Sara Trova, Monica Imbernon, Laurine Decoster, Ludovica Cotellessa, Manuel Tena-Sempere, Marc Claret, Ariane Paoloni-Giacobino, Damien Plassard, Emmanuelle Paccou, Nathalie Vionnet, James Acierno, Aleksandra Maleska Maceski, Antoine Lutti, Frank Pfrieger, S. Rasika, Federico Santoni, Ulrich Boehm, Philippe Ciofi, Luc Buée, Nasser Haddjeri, Anne-Laurence Boutillier, Jens Kuhle, Andrea Messina, Bogdan Draganski, Paolo Giacobini, Nelly Pitteloud, Vincent Prevot, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Excellence Laboratory LabEx DISTALZ, FHU 1,000 Days for Health [Lille], Université de Lille, European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Lausanne University Hospital, Université de Lausanne = University of Lausanne (UNIL), Laboratoire de neurosciences cognitives et adaptatives (LNCA), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (U1208 Inserm - UCBL1 / SBRI - USC 1361 INRAE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Saarland University [Saarbrücken], Instituto de Salud Carlos III [Madrid] (ISC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Hospital Basel [Basel], University of Basel (Unibas), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, Prevot, Vincent, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (SBRI), and ANR-17-CE16-0015,GRAND,Vieillissement et démence: un rôle hormonal?(2017)

Subjects
Adult, Male, Multidisciplinary, [SDV]Life Sciences [q-bio], Hypothalamus, Middle Aged, Synaptic Transmission, Article, Gonadotropin-Releasing Hormone, Disease Models, Animal, Mice, Olfaction Disorders, Young Adult, Cognition, Alzheimer Disease, Animals, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive Dysfunction, Female, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Down Syndrome
Abstract

International audience; At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction—gonadotropin-releasing hormone (GnRH)—and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

Published
2022
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18. SUPT3H-less SAGA coactivator can assemble and function without significantly perturbing RNA polymerase II transcription in mammalian cells

Author

Veronique Fischer, Vincent Hisler, Elisabeth Scheer, Elisabeth Lata, Bastien Morlet, Damien Plassard, Dominique Helmlinger, Didier Devys, László Tora, Stéphane D Vincent, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme GenomEast [Illkrch], Infrastructure France Génomique, Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and VINCENT, Stéphane

Subjects
Saccharomyces cerevisiae Proteins, Transcription, Genetic, Saccharomyces cerevisiae, DNA-Binding Proteins, Histones, Mice, Trans-Activators, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA Polymerase II, Histone Acetyltransferases, Transcription Factors
Abstract

Coactivator complexes regulate chromatin accessibility and transcription. SAGA (Spt-Ada-Gcn5 Acetyltransferase) is an evolutionary conserved coactivator complex. The core module scaffolds the entire SAGA complex and adopts a histone octamer-like structure, which consists of six histone-fold domain (HFD)-containing proteins forming three histone-fold (HF) pairs, to which the double HFD-containing SUPT3H adds one HF pair. Spt3, the yeast ortholog of SUPT3H, interacts genetically and biochemically with the TATA binding protein (TBP) and contributes to global RNA polymerase II (Pol II) transcription. Here we demonstrate that (i) SAGA purified from human U2OS or mouse embryonic stem cells (mESC) can assemble without SUPT3H, (ii) SUPT3H is not essential for mESC survival, but required for their growth and self-renewal, and (iii) the loss of SUPT3H from mammalian cells affects the transcription of only a specific subset of genes. Accordingly, in the absence of SUPT3H no major change in TBP accumulation at gene promoters was observed. Thus, SUPT3H is not required for the assembly of SAGA, TBP recruitment, or overall Pol II transcription, but plays a role in mESC growth and self-renewal. Our data further suggest that yeast and mammalian SAGA complexes contribute to transcription regulation by distinct mechanisms.

Published
2022
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19. The S. cerevisiae m6A-reader Pho92 promotes timely meiotic recombination by controlling key methylated transcripts

Author

Jérémy Scutenaire, Damien Plassard, Mélody Matelot, Tommaso Villa, Julie Zumsteg, Domenico Libri, Bertrand Séraphin, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Villa, Tommaso

Subjects
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Abstract

N6-Methyladenosine (m6A), one of the most abundant internal modification of eukaryotic mRNAs, participates in the post-transcriptional control of gene expression through recruitment of specific m6A readers. In Saccharomyces cerevisiae, the m6A methyltransferase Ime4 is expressed only during meiosis and its deletion impairs this process. To elucidate how m6A control gene expression, we investigated the function of the budding yeast m6A reader Pho92. We show that Pho92 is an early meiotic factor that promotes timely meiotic progression. High-throughput RNA sequencing and mapping of Pho92-binding sites following UV-crosslinking reveal that Pho92 is recruited to specific mRNAs in an m6A-dependent manner during the meiotic prophase, preceding their down-regulation. Strikingly, point mutations altering m6A sites in mRNAs targeted by Pho92 are sufficient to delay their down-regulation and, in one case, to slow down meiotic progression. Altogether, our results indicate that Pho92 facilitate the meiotic progression by accelerating the down-regulation of timely-regulated mRNAs during meiotic recombination.mRNAs molecules carry information contained in genes to direct the formation of proteins. In specific circumstances, the cellular machinery modifies some mRNAs through the formation of m6A residues. To understand the function of these m6A marks, the authors used the yeast Saccharomyces cerevisiae in which their formation only occurs during meiosis that leads to spore formation. Characterization of the Pho92 protein that specifically recognizes m6A residues revealed its importance for meiosis. m6A sites bound by Pho92 were identified and shown to be biologically functional. Unexpectedly, Pho92 was found to regulate an early step of meiosis by controlling DNA recombination. Overall, this study provides important clues on the role of m6A residues in mRNAs.

Published
2022
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20. Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome

Author

Jérémie Courraud, Camille Engel, Angélique Quartier, Nathalie Drouot, Ursula Houessou, Damien Plassard, Arthur Sorlin, Elise Brischoux-Boucher, Lionel Van Maldergem, Evan Gouy, Massimiliano Rossi, Patrick Edery, Audrey Putoux, Brigitte Gilbert-Dussardier, Vera Kalscheuer, Jean-Louis Mandel, and Amélie Piton

Abstract

Mutations in the PQBP1 gene (polyglutamine-binding protein 1) are responsible for a syndromic X-linked form of intellectual disability (XLID), the Renpenning syndrome. PQBP1 encodes a protein that plays a role in the regulation of gene expression, splicing and mRNA translation. To investigate the consequences of variants in PQBP1, we performed transcriptomic studies in 1) patients’ lymphoblastoid cell lines (LCL) carrying pathogenic variants in PQBP1 and 2) in human neural stem cells (hNSC) knocked-down (KD) for PQBP1. This led to the identification of a hundred dysregulated genes. In particular, we identified an increase in the expression of a non-canonical isoform of another XLID gene, UPF3B. UPF3B plays a crucial role during neurodevelopment by coding for an important actor of the nonsense mRNA mediated decay (NMD) system involved in regulation of protein translation, however, the exact function of the non-canonical isoform,UPF3B_S, is currently unknown. In order to investigate the role of UPF3B_S isoform, we compared the protein interactome of UPF3B_S to the canonical isoform (UPF3B_L). We confirmed that, on the contrary to UPF3B_L, UPF3B_S does not interact with the UPF2/UPF1 complex while it still interacts with exon junction complexes (EJC). However, no notable decrease of NMD pathways was observed in patient’s LCL or in hNSC KD for PQBP1. We identified several additional protein interactors specific to UPF3B_S. Moreover, we used the increase of UPF3B_S mRNA as a molecular marker to test the pathogenicity of variants of unknown clinical significance identified in individuals with ID in PQPB1. We analyzed patients’ LCL mRNA as well as blood mRNA samples and performed complementation studies in HeLa cells by overexpressing Wild-type and mutant PQBP1 cDNA. We showed that all these three approaches were efficient to test the effect of variants, at least for variants affecting the CTD domain of the protein. In conclusion, our study provides information on how PQBP1 deficiency may affect the expression of genes and isoforms, such as UPF3B. This informs about the pathological mechanisms involved in Renpenning syndrome but also allows to propose a functional test for variants of unknown significance identified in PQBP1.

Published
2022
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22. The S. cerevisiae m6A-reader Pho92 impacts meiotic recombination by controlling key methylated transcripts

Author

Jérémy Scutenaire, Damien Plassard, Mélody Matelot, Tommaso Villa, Julie Zumsteg, Domenico Libri, and Bertrand Séraphin

Abstract

SUMMARYN6-methyladenosine (m6A), the most abundant internal modification of eukaryotic mRNAs, participates in the post-transcriptional control of gene expression. In Saccharomyces cerevisiae, m6A is only found during meiosis. Although the deletion of the m6A- methyltransferase Ime4 impairs this process, the molecular impact of m6A on gene expression remains ill defined. Here we investigated the function of the budding yeast m6A reader Pho92. We found that Pho92 is specifically expressed during meiosis and impacts meiotic progression. We used high-throughput RNA sequencing and mapping of Pho92-binding sites following UV-crosslinking to show that Pho92 is recruited to specific mRNAs in an m6A-dependent manner during the meiotic prophase, preceding their down-regulation. Strikingly, point mutations altering m6A sites in mRNAs targeted by Pho92 are sufficient to delay their down-regulation and, in one case, to impact meiotic progression. Altogether, our results indicate that Pho92 facilitate the meiotic progression by accelerating the down-regulation of timely-regulated mRNAs during meiotic recombination.

Published
2022
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23. Photoreceptor cKO of OTX2 Enhances OTX2 Intercellular Transfer in the Retina and Causes Photophobia

Author

Annabelle Mantilleri, Alain Prochiantz, Thomas Lamonerie, Damien Plassard, Pasquale Pensieri, Kenneth L. Moya, Takahisa Furukawa, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Osaka University [Osaka], Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), MOYA, Kenneth, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)

Subjects
Photoreceptors, retina, Mouse, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Endogeny, Chromosomal translocation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Homeoprotein transfer, Mice, chemistry.chemical_compound, Photophobia, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Gene expression, medicine, Transcriptional regulation, Animals, Photoreceptor Cells, Cytoskeleton, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Retina, Otx Transcription Factors, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Neuroscience, Retinal Degeneration, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Retinal, General Medicine, eye diseases, Cell biology, Arrestin-1, medicine.anatomical_structure, chemistry, Cytoplasm, Sensory and Motor Systems, Retina Significance Statement, sense organs, Research Article: New Research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Otx2
Abstract

In the mature mouse retina, Otx2 is expressed in both Retinal Pigmented Epithelium (RPE) and photoreceptor (PR) cells, but Otx2 knockout in the RPE alone results in PR degeneration. To study the cell-autonomous function of OTX2 in PRs, we performed PR-specific Otx2 knockout (cKO) in adults. As expected, the protein disappears completely from PR nuclei but is still observed in PR inner and outer segments while its level concomitantly decreases in the RPE, suggesting a transfer of OTX2 from RPE to PRs in response to Otx2 ablation in PRs. The ability of OTX2 to transfer from RPE to PRs was verified by viral expression of tagged-OTX2 in the RPE. Transferred OTX2 distributed across the PR cytoplasm, suggesting functions distinct from nuclear transcription regulation functions. PR-specific Otx2 cKO did not alter the structure of the retina but impaired the translocation of photoreceptor arrestin-1 upon illumination changes, making mice photophobic. RNA-seq analyses following Otx2 knockout revealed down-regulation of genes involved in the cytoskeleton that might account for the arrestin-1 translocation defect, and of genes involved in extracellular matrix and signalling factors that may participate in the enhanced transfer of OTX2. Interestingly, several RPE-specific OTX2 target genes involved in melanogenesis were downregulated, lending weight to a decrease of OTX2 levels in the RPE following PR-specific Otx2 cKO. Our study reveals a new role of endogenous OTX2 in PR light adaptation and demonstrates the existence of OTX2 transfer from RPE to PR cells, which is increased upon PR-specific Otx2 ablation and might participate in PR neuroprotection.Significance statementOTX2 homeoprotein is expressed in retinal pigmented epithelium (RPE), photoreceptors (PRs) and bipolar cells. The function of endogenous PR OTX2, which, in contrast with RPE OTX2, is dispensable for PR maintenance, is unknown. We performed PR-specific Otx2 knockout and found that removal of endogenous PR OTX2 leads to impaired arrestin-1 translocation associated with photophobia, specific modifications of PR and RPE gene expression, and to increased transfer of OTX2 protein from the RPE to the PR cytoplasm. Thus, several PR activities, including light adaptation, rely on endogenous nuclear OTX2, while PR neuroprotection seems to require RPE OTX2, highlighting the importance of non-cell-autonomous OTX2 in the adult retina.

Published
2021
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24. Analysis of the transcriptome of bovine endometrial cells isolated by laser micro-dissection (2): impacts of post-partum negative energy balance on stromal, glandular and luminal epithelial cells

Author

Patrice Humblot, Gilles Charpigny, Olivier Sandra, Mariam Raliou, Wiruntita Chankeaw, Göran Andersson, Claudia Bevilacqua, Yongzhi Guo, Christophe Richard, Theodoros Ntallaris, Sandra Lignier, Damien Plassard, Swedish University of Agricultural Sciences (SLU), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Animal Bredding and Genetics, FP7-KBBE-2012-6 Prolific and Grant agreement number 311776/Seventh Framework Programme, Charpigny, gilles, Collaborative Research: Sediment Nanomagnetism and Environmental Change: The Microbial Mineral Link - 2003-09-01 - 2007-08-31 - 0311776 - VALID, Rajamangala University of Technology Thanyaburi (RMUTT), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), European Project: 0311776(2003), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
Cell type, Stromal cell, Negative energy balance, RNA-Seq, Biology, QH426-470, Transcriptome, Andrology, 03 medical and health sciences, Endometrium, Pregnancy, Animal and Dairy Science, Cell type-specific, Gene expression, Genetics, Animals, Humans, Lactation, Gene, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, Inflammation, 0303 health sciences, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Dissection, Lasers, Postpartum Period, 0402 animal and dairy science, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Embryo, Epithelial Cells, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, LCM, 04 agricultural and veterinary sciences, Acquired immune system, 040201 dairy & animal science, Cattle, Female, RNA-seq, Energy Metabolism, TP248.13-248.65, Research Article, Biotechnology
Abstract

Background In post-partum dairy cows, the energy needs to satisfy high milk production induces a status of more or less pronounced Negative Energy Balance (NEB). NEB associated with fat mobilization impairs reproductive function. In a companion paper, we described constitutive gene expression in the three main endometrial cell types (stromal, glandular and luminal epithelial cells) isolated by laser capture micro-dissection (LCM) showing the specificities of their transcriptomic profiles. This study investigates the specific impact of NEB on gene expression in these cells around 80 days after parturition at day 15 of the oestrus cycle and describes their specific response to NEB. Results Following the description of their constitutive expression, the transcriptome profiles obtained by RNA sequencing of the three cells types revealed that differences related to the severity of NEB altered mainly specific patterns of expression related to individual cell types. Number of differentially expressed genes between severe NEB (SNEB) and mild NEB (MNEB) cows was higher in ST than in LE and GE, respectively. SNEB was associated with differential expression of genes coding for proteins involved in metabolic processes and embryo-maternal interactions in ST. Under-expression of genes encoding proteins with functions related to cell structure was found in GE whereas genes encoding proteins participating in pro-inflammatory pathways were over-expressed. Genes associated to adaptive immunity were under-expressed in LE. Conclusion The severity of NEB after calving is associated with changes in gene expression around 80 days after parturition corresponding to the time of breeding. Specific alterations in GEs are associated with activation of pro-inflammatory mechanisms. Concomitantly, changes in the expression of genes encoding proteins involved in cell interactions and maternal recognition of pregnancy takes place in ST. The combination of these effects possibly altering the uterine environment and embryo maternal interactions may negatively influence the establishment of pregnancy.

Published
2021
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25. Analysis of the transcriptome of bovine endometrial cells isolated by laser micro-dissection (1): specific signatures of stromal, glandular and luminal epithelial cells

Author

Christophe Richard, Olivier Sandra, Theodoros Ntallaris, Gilles Charpigny, Wiruntita Chankeaw, Yongzhi Guo, Sandra Lignier, Patrice Humblot, Göran Andersson, Mariam Raliou, Claudia Bevilacqua, Damien Plassard, Swedish University of Agricultural Sciences (SLU), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Animal Bredding and Genetics, 311776/FP7-KBBE-2016-6, PROLIFIC, Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Charpigny, gilles, Collaborative Research: Sediment Nanomagnetism and Environmental Change: The Microbial Mineral Link - 2003-09-01 - 2007-08-31 - 0311776 - VALID, École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and European Project: 0311776(2003)

Subjects
Cell signaling, Stromal cell, Biology, QH426-470, Endometrium, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Cell type-specific, medicine, Genetics, Animals, Embryo Implantation, Cell adhesion, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, Enzyme linked receptor protein signaling pathway, 0303 health sciences, 030219 obstetrics & reproductive medicine, Dissection, Lasers, Cow, Cilium movement, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, LCM, Epithelial Cells, Clinical Science, Cell biology, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, medicine.anatomical_structure, Cattle, Female, RNA-seq, Stromal Cells, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, TP248.13-248.65, Extracellular matrix organization, Biotechnology, Research Article
Abstract

Background A number of studies have examined mRNA expression profiles of bovine endometrium at estrus and around the peri-implantation period of pregnancy. However, to date, these studies have been performed on the whole endometrium which is a complex tissue. Consequently, the knowledge of cell-specific gene expression, when analysis performed with whole endometrium, is still weak and obviously limits the relevance of the results of gene expression studies. Thus, the aim of this study was to characterize specific transcriptome of the three main cell-types of the bovine endometrium at day-15 of the estrus cycle. Results In the RNA-Seq analysis, the number of expressed genes detected over 10 transcripts per million was 6622, 7814 and 8242 for LE, GE and ST respectively. ST expressed exclusively 1236 genes while only 551 transcripts were specific to the GE and 330 specific to LE. For ST, over-represented biological processes included many regulation processes and response to stimulus, cell communication and cell adhesion, extracellular matrix organization as well as developmental process. For GE, cilium organization, cilium movement, protein localization to cilium and microtubule-based process were the only four main biological processes enriched. For LE, over-represented biological processes were enzyme linked receptor protein signaling pathway, cell-substrate adhesion and circulatory system process. Conclusion The data show that each endometrial cell-type has a distinct molecular signature and provide a significantly improved overview on the biological process supported by specific cell-types. The most interesting result is that stromal cells express more genes than the two epithelial types and are associated with a greater number of pathways and ontology terms.

Published
2021
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26. The related coactivator complexes SAGA and ATAC control embryonic stem cell self-renewal through acetyltransferase-independent mechanisms

Author

Tao Ye, Matthieu Stierle, Didier Devys, Laszlo Tora, Bernardo Reina-San-Martin, Veronique Fischer, Damien Plassard, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Tora, Laszlo

Subjects
Saccharomyces cerevisiae Proteins, QH301-705.5, Protein subunit, mouse embryonic stem cells, coactivator complexes, SAGA, RNA polymerase II, Saccharomyces cerevisiae, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Article, General Biochemistry, Genetics and Molecular Biology, Histones, Mice, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Coactivator, parasitic diseases, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell Self Renewal, Biology (General), Embryonic Stem Cells, Histone Acetyltransferases, 030304 developmental biology, 0303 health sciences, biology, Histone acetyltransferase, 4sU labeling, Phenotype, Embryonic stem cell, ATAC, 3. Good health, Cell biology, enzymes and coenzymes (carbohydrates), Acetyltransferase, embryonic structures, Trans-Activators, biology.protein, RNA Polymerase II, Protein Processing, Post-Translational, Pol II transcription, 030217 neurology & neurosurgery
Abstract

SUMMARY SAGA (Spt-Ada-Gcn5 acetyltransferase) and ATAC (Ada-two-A-containing) are two related coactivator complexes, sharing the same histone acetyltransferase (HAT) subunit. The HAT activities of SAGA and ATAC are required for metazoan development, but the role of these complexes in RNA polymerase II transcription is less understood. To determine whether SAGA and ATAC have redundant or specific functions, we compare the effects of HAT inactivation in each complex with that of inactivation of either SAGA or ATAC core subunits in mouse embryonic stem cells (ESCs). We show that core subunits of SAGA or ATAC are required for complex assembly and mouse ESC growth and self-renewal. Surprisingly, depletion of HAT module subunits causes a global decrease in histone H3K9 acetylation, but does not result in significant phenotypic or transcriptional defects. Thus, our results indicate that SAGA and ATAC are differentially required for self-renewal of mouse ESCs by regulating transcription through different pathways in a HAT-independent manner., In brief Fischer et al. analyze the role of SAGA and ATAC coactivator complexes that share a histone acetyltransferase (HAT) subunit in mouse embryonic stem cells (ESCs). The authors separate the core and HAT activities of these complexes to show that they play non-redundant roles in maintaining ESCs, through HAT-independent pathways., Graphical Abstract

Published
2021
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27. Two Related Coactivator Complexes SAGA and ATAC Control Embryonic Stem Cell Self-Renewal Through Two Different Acetyltransferase-Independent Mechanisms

Author

Matthieu Stierle, Laszlo Tora, Bernardo Reina San Martin, Didier Devys, Veronique Fischer, Tao Ye, and Damien Plassard

Subjects
Transcription (biology), Protein subunit, Acetyltransferase, parasitic diseases, embryonic structures, Coactivator, biology.protein, RNA polymerase II, Histone acetyltransferase, Biology, Gene, Embryonic stem cell, Cell biology
Abstract

SAGA and ATAC are two related transcriptional coactivator complexes, sharing the same histone acetyltransferase (HAT) subunit. The HAT activities of SAGA and ATAC are required for metazoan development but the precise role of the two complexes in RNA polymerase II transcription in mammals is less understood. To determine whether SAGA and ATAC have redundant or specific functions dependent on their HAT activities, we compared the effects of HAT inactivation in each complex with that of complete inactivation of either SAGA or ATAC in mouse embryonic stem cells (ESCs) . We show that core subunits of SAGA or ATAC subunits are required for complex assembly, mouse ESC growth and self-renewal. Additionally, ATAC, but not SAGA subunits are required for ESC viability by regulating the transcription of translation-related genes. Surprisingly, depletion of a shared or specific HAT module subunits caused a global decrease in histone H3K9 acetylation, but did not result in significant phenotypic or transcriptional defects. Thus, our results indicate that SAGA and ATAC are differentially required for viability and self-renewal of mouse ESCs by regulating transcription through different pathways, but in a HAT-independent manner.

Published
2021
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29. Impact of negative energy balance on transcriptomic profiles of three endometrial cell types isolated by laser capture microdissection in postpartum dairy cows

Author

Gilles Charpigny, Damien Plassard, Theodoros Ntallaris, Sandra Lignier, Olivier Sandra, Christophe Richard, Göran Andersson, Mariam Raliou, Claudia Bevilacqua, Wiruntita Chankeaw, Yongzhi Guo, and Patrice Humblot

Subjects
Transcriptome, Andrology, Biology, Balance (ability), Endometrial cell, Laser capture microdissection
Abstract

Background: In postpartum dairy cows, the energy needs to satisfy high milk production induces a more or less pronounced Negative Energy Balance (NEB) status. NEB associated with fat mobilization impairs reproductive function. This study investigated the specific impact of NEB on gene expression in the three main types of endometrial cells at time planned for insemination and implantation. Endometrial cell types (stromal, glandular and luminal epithelial cells) were isolated by laser micro-dissection allowing the study of constitutive gene expression and their specific response to NEB. Methods: Nine Swedish Red cows receiving a control diet or a mild restricted diet to induce differences of energy balance were categorized into mild (MNEB, n = 5) and severe negative energy balance (SNEB, n = 4). The three endometrial cell types: luminal (LE), glandular (GE) epithelium and stroma (ST) were collected by laser microdissection from endometrial biopsies performed at 80 days postpartum. Results: Transcriptome profiles obtained by RNA sequencing revealed differences in constitutive gene expression between the three cells types and also differences in specific responses related to the severity of NEB. Number of differentially expressed genes between SNEB and MNEB cows was higher in ST than in LE and GE, respectively. SNEB was associated with differential expression of genes related to metabolic processes and embryo-maternal interactions in ST. Under-expression of genes related to cell structure was found in GE whereas genes related to pro-inflammatory pathways were over-expressed. Genes associated to adaptive immunity were under-expressed in LE. Conclusion: The three different main cells types of the endometrium, have very different patterns of gene expression. The severity of NEB after calving is associated with changes in gene expression at time of breeding. Specific alterations in GEs are associated with activation of pro-inflammatory mechanisms. Concomitantly, changes in the expression of genes related to cell to cell interactions and maternal recognition of pregnancy takes place in ST. The combination of these effects possibly altering the uterine environment and embryo maternal interactions may negatively influence the establishment of pregnancy.

Published
2020
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30. Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish

Author

Fouzia Studer, Corinne Stoetzel, Jean Muller, Amélie Piton, Aline Schneider, Olivier Poch, Christelle Etard, Damien Plassard, Clarisse Delvallée, Sabine Sigaudy, Hélène Dollfus, Alejandro Estrada-Cuzcano, Uwe Strähle, Elise Schaefer, Francesca Mattioli, Sophie Scheidecker, Kirsley Chennen, Véronique Geoffroy, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte, École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Fluorescent Antibody Technique, [SDV.GEN] Life Sciences [q-bio]/Genetics, Ciliopathies, Pronephric duct, Sciences du Vivant [q-bio]/Génétique, Fingers, Consanguinity, 03 medical and health sciences, Exome Sequencing, Sciences du Vivant [q-bio]/Biologie cellulaire, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Gene, Zebrafish, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polydactyly, biology, Gene Expression Profiling, Cilium, Homozygote, 030305 genetics & heredity, Haplotype, Intracellular Signaling Peptides and Proteins, Genetic Variation, Membrane Proteins, Toes, medicine.disease, biology.organism_classification, Immunohistochemistry, Phenotype, Pedigree, 3. Good health, Transcriptome, Signal Transduction
Abstract

Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high-genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole-exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients' fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog-signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left-right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.

Published
2019
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31. µgreen-db: a reference database for the 23S rRNA gene of eukaryotic plastids and cyanobacteria

Author

Samuel Mondy, Damien Plassard, Joana Sauze, Virginie Nowak, Olivier Crouzet, Pierre-Alain Maron, Lisa Wingate, Jérôme Ogée, Sébastien Terrat, Christophe Djemiel, Agroécologie [Dijon], Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Ecologie fonctionnelle et écotoxicologie des agroécosystèmes (ECOSYS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Interactions Sol Plante Atmosphère (UMR ISPA), Ecole Nationale Supérieure des Sciences Agronomiques de Bordeaux-Aquitaine (Bordeaux Sciences Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), European Research Council (ERC), INRA Départements EA et EFPA, ANR-13-BS06-0005,ORCA,Etude des mécanismes de régulation de l'anhydrase carbonique et des flux de COS et CO18O dans les écosystèmes terrestres(2013), DESAILLY, Marion, Blanc 2013 - Etude des mécanismes de régulation de l'anhydrase carbonique et des flux de COS et CO18O dans les écosystèmes terrestres - - ORCA2013 - ANR-13-BS06-0005 - Blanc 2013 - VALID, and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDE] Environmental Sciences, 0106 biological sciences, 0301 basic medicine, Cyanobacteria, Molecular biology, [SDV]Life Sciences [q-bio], lcsh:Medicine, Computational biology, 010603 evolutionary biology, 01 natural sciences, Microbiology, Article, Microeucaryote, 03 medical and health sciences, Soil, Genus, 23S ribosomal RNA, DNA Barcoding, Taxonomic, Marqueur génétique, Plastids, Plastid, Photosynthesis, lcsh:Science, Gene, Multidisciplinary, biology, Ecology, lcsh:R, Eukaryota, AlgaeBase, 15. Life on land, biology.organism_classification, DNA, Environmental, Computational biology and bioinformatics, RNA, Ribosomal, 23S, 030104 developmental biology, Genetic marker, [SDE]Environmental Sciences, Taxonomy (biology), lcsh:Q, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Databases, Nucleic Acid
Abstract

Studying the ecology of photosynthetic microeukaryotes and prokaryotic cyanobacterial communities requires molecular tools to complement morphological observations. These tools rely on specific genetic markers and require the development of specialised databases to achieve taxonomic assignment. We set up a reference database, called µgreen-db, for the 23S rRNA gene. The sequences were retrieved from generalist (NCBI, SILVA) or Comparative RNA Web (CRW) databases, in addition to a more original approach involving recursive BLAST searches to obtain the best possible sequence recovery. At present, µgreen-db includes 2,326 23S rRNA sequences belonging to both eukaryotes and prokaryotes encompassing 442 unique genera and 736 species of photosynthetic microeukaryotes, cyanobacteria and non-vascular land plants based on the NCBI and AlgaeBase taxonomy. When PR2/SILVA taxonomy is used instead, µgreen-db contains 2,217 sequences (399 unique genera and 696 unique species). Using µgreen-db, we were able to assign 96% of the sequences of the V domain of the 23S rRNA gene obtained by metabarcoding after amplification from soil DNA at the genus level, highlighting good coverage of the database. µgreen-db is accessible at http://microgreen-23sdatabase.ea.inra.fr.

Published
2019
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32. A new genetically engineered mouse model of choroid plexus carcinoma

Author

Thomas Lamonerie, Salsabiel El Nagar, Nathalie Billon, Frederique Zindy, Charlotte Moens, Luc Martin, Martine F. Roussel, Damien Plassard, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), St Jude Children's Research Hospital, Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Nathalie, Billon

Subjects
0301 basic medicine, Choroid Plexus Neoplasms, Cell division, Carcinogenesis, Trp53, mouse model, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biophysics, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Myc, medicine.disease_cause, Biochemistry, Article, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Mice, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, Choroid plexus carcinoma, medicine, Carcinoma, Animals, Humans, Molecular Biology, Cell Proliferation, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Cell growth, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell Biology, medicine.disease, Disease Models, Animal, 030104 developmental biology, paediatric cancer, Genetically Engineered Mouse, Choroid Plexus, Mutation, Cancer research, Choroid plexus, Choroid Plexus Neoplasm, Tumor Suppressor Protein p53, Transcriptome, DNA Damage, Otx2
Abstract

International audience; Choroid plexus carcinomas (CPCs) are highly malignant brain tumours predominantly found in children and associated to poor prognosis. Improved therapy for these cancers would benefit from the generation of animal models. Here we have created a novel mouse CPC model by expressing a stabilised form of c-Myc (MycT58A) and inactivating Trp53 in the choroid plexus of newborn mice. This induced aberrant proliferation of choroid plexus epithelial cells, leading to aggressive tumour development and death within 150 days. Choroid plexus tumours occurred with a complete penetrance in all brain ventricles, with prevalence in the lateral and fourth ventricles. Histological and cellular analysis indicated that these tumours were CPCs resembling their human counterparts. Comparison of gene expression profiles of CPCs and non-neoplastic tissues revealed profound alterations in cell cycle regulation and DNA damage responses, suggesting that dysregulation of cell division and DNA checkpoint pathways may represent key vulnerabilities. This novel animal model of CPC provides an invaluable tool to elucidate the mechanism of CPC formation and to develop successful therapies against this devastating paediatric cancer.

Published
2018
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33. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Florian R. T., Kraft F., Leitao E., Kaya S., Klebe S., Magnin E., van Rootselaar A. -F., Buratti J., Kuhnel T., Schroder C., Giesselmann S., Tschernoster N., Altmueller J., Lamiral A., Keren B., Nava C., Bouteiller D., Forlani S., Jornea L., Kubica R., Ye T., Plassard D., Jost B., Meyer V., Deleuze J. -F., Delpu Y., Avarello M. D. M., Vijfhuizen L. S., Rudolf G., Hirsch E., Kroes T., Reif P. S., Rosenow F., Ganos C., Vidailhet M., Thivard L., Mathieu A., Bourgeron T., Kurth I., Rafehi H., Steenpass L., Horsthemke B., Berkovic S. F., Bisulli F., Brancati F., Canafoglia L., Casari G., Guerrini R., Ishiura H., Licchetta L., Mei D., Pippucci T., Sadleir L., Scheffer I. E., Striano P., Tinuper P., Tsuji S., Zara F., LeGuern E., Klein K. M., Labauge P., Bennett M. F., Bahlo M., Gecz J., Corbett M. A., Tijssen M. A. J., van den Maagdenberg A. M. J. M., Depienne C., Florian, R. T., Kraft, F., Leitao, E., Kaya, S., Klebe, S., Magnin, E., van Rootselaar, A. -F., Buratti, J., Kuhnel, T., Schroder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J. -F., Delpu, Y., Avarello, M. D. M., Vijfhuizen, L. S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P. S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpass, L., Horsthemke, B., Berkovic, S. F., Bisulli, F., Brancati, F., Canafoglia, L., Casari, G., Guerrini, R., Ishiura, H., Licchetta, L., Mei, D., Pippucci, T., Sadleir, L., Scheffer, I. E., Striano, P., Tinuper, P., Tsuji, S., Zara, F., Leguern, E., Klein, K. M., Labauge, P., Bennett, M. F., Bahlo, M., Gecz, J., Corbett, M. A., Tijssen, M. A. J., van den Maagdenberg, A. M. J. M., Depienne, C., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), genomic vision, Leiden University Medical Center (LUMC), Universiteit Leiden, Centre de référence des épilepsies rares [CHRU Strasbourg] (CRéER), Centre Hospitalier Régional Universitaire de Strasbourg (CHRU de Strasbourg), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, School of Biological Sciences [Adelaïde], University of Adelaide, Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Epilepsy Research Centre, University of Calgary, Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), University Medical Center Groningen [Groningen] (UMCG), This study has been financially supported by three different grants from the Fondation Maladies rares to C.D. (2009, 2010, 2016), Assistance Publique des Hôpitaux de Paris (APHP), INSERM, the 'Investissements d’Avenir' programme ANR-10-IAIHU-06 (IHU-A-ICM), University Duisburg-Essen and University Hospital Essen. M.B. was supported by an Australian National Health and Medical Research Council (NHMRC) Program Grant (GNT1054618) and an NHMRC Senior Research Fellowship (GNT1102971). This work was also supported by the Victorian Government’s Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS). Laura Canafoglia: Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE., We thank the families for their participation in this study, Agnès Rastetter (ICM, Paris, France) for RNA extraction, and Emmanuelle Apartis (Hôpital Saint-Antoine, Paris, France) for electrophysiological assessment of Family 1. DNA extraction and cell culture of lymphoblasts have been performed at the DNA and cell bank of ICM (Paris, France). RNA-seq has been performed on the GenomEast platform of IGBMC, Illkirch, France. WGS has been performed by the Centre National de Recherche en Génomique Humaine (CNRGH) Institut de Biologie François Jacob, Evry, France. We thank Jean-Louis Mandel and Nicolas Charlet-Berguerand (IGBMC, Strasbourg, France), Cécile Cazeneuve (Hôpital Pitié-Salpêtrière, Paris, France), Charles Marcaillou (Integragen, Evry, France) and Isabel Silveira (Porto, Portugal) for valuable discussions., FAME consortium : Berkovic SF, Bisulli F, Brancati F, Canafoglia L, Casari G, Guerrini R, Ishiura H, Licchetta L, Mei D, Pippucci T, Sadleir L, Scheffer IE, Striano P, Tinuper P, Tsuji S, Zara F., Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), RWTH Aachen University, Universität Duisburg-Essen [Essen], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Philipps University of Marburg, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D.M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A.J. Tijssen, Arn M.J.M. van den Maagdenberg, Christel Depienne, Francesca Bisulli, Laura Licchetta, Paolo Tinuper, MATHIEU, Alexandre, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Male, MESH: Introns, [SDV]Life Sciences [q-bio], Medizin, MESH: DNA Repeat Expansion, Epilepsies, Myoclonic, [SDV.GEN] Life Sciences [q-bio]/Genetics, MARCH6, expansion, MESH: Ubiquitin-Protein Ligases/genetics, MESH: Aged, MESH: Middle Aged, DNA Repeat Expansion, Neurodegenerative diseases, MESH: Epilepsies, Myoclonic, Chromosome Mapping, Middle Aged, MESH: Epilepsies, Myoclonic/genetics, Pedigree, MESH: Young Adult, Female, ddc:500, MESH: Membrane Proteins, Technology Platforms, Genomic instability, Adult, Adolescent, MESH: Pedigree, Ubiquitin-Protein Ligases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Familial Adult Myoclonic Epilepsy type 3, Article, Young Adult, Humans, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Epilepsy, Membrane Proteins, MESH: Adult, MESH: Membrane Proteins/genetics, MESH: Ubiquitin-Protein Ligases, MESH: Male, Introns, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Chromosome Mapping, MESH: Female, Neurological disorders
Abstract

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements., Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.

Published
2019
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