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Your search keyword '"Dayana C Farhat"' showing total 4 results
Start Over Author "Dayana C Farhat" Topic 0303 health sciences
4 results on '"Dayana C Farhat"'

1. The developmental trajectories of Toxoplasma stem from an elaborate epigenetic rewiring

Author

Dayana C. Farhat and Mohamed-Ali Hakimi

Subjects
Flexibility (engineering), 0303 health sciences, Life Cycle Stages, media_common.quotation_subject, Biology, biology.organism_classification, Unicellular organism, Adaptability, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Evolutionary biology, Animals, Parasitology, Parasites, Epigenetics, Reprogramming, Toxoplasma, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract

Toxoplasma gondii is considered to be one of the most successful parasitic pathogens. It owes this success to its flexibility in responding to signals emanating from the different environments it encounters during its multihost life cycle. The adaptability of this unicellular organism relies on highly coordinated and evolutionarily optimized developmental abilities that allow it to adopt the forms best suited to the requirements of each environment. Here we discuss recent outstanding studies that have uncovered how master regulators epigenetically regulate the cryptic process of sexual development and the transition to chronicity. We also highlight the molecular and technical advances that allow the field to embark on a new journey of epigenetic reprogramming of T. gondii development.

Published
2021

2. A plant-like mechanism coupling m6A reading to polyadenylation safeguards transcriptome integrity and developmental genes partitioning inToxoplasma

Author

Thierry Lagrange, Guillaume Communie, Alexandre Bougdour, Dominique Pontier, Yohann Couté, Dayana C. Farhat, Christopher Swale, Matthew W. Bowler, Caroline Mas, Lucid Belmudes, Charlotte Corrao, and Mohamed-Ali Hakimi

Subjects
0303 health sciences, Polyadenylation, RNA, Biology, biology.organism_classification, Phenotype, Cell biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Arabidopsis thaliana, Polyadenylation Pathway, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Correct 3’end processing of mRNAs is regarded as one of the regulatory cornerstones of gene expression. In a parasite that must answer to the high regulatory requirements of its multi-host life style, there is a great need to adopt additional means to partition the distinct transcriptional signatures of the closely and tandemly-arranged stage specific genes. In this study, we report on our findings inT. gondiiof an m6A-dependent 3’end polyadenylation serving as a transcriptional barrier at theseloci. We identify the core polyadenylation complex withinT. gondiiand establish CPSF4 as a reader for m6A-modified mRNAs, via a YTH domain within its C-terminus, a feature which is shared with plants. We bring evidence of the specificity of this interaction both biochemically, and by determining the crystal structure at high resolution of theT. gondiiCPSF4-YTH in complex with an m6A modified RNA. We show that the loss of m6A, both at the level of its deposition or its recognition was associated with an increase in aberrantly elongated chimeric mRNAs emanating from impaired transcriptional termination, a phenotype previously noticed in the plant modelArabidopsis thaliana. We bring Nanopore direct RNA sequencing-based evidence of the occurrence of transcriptional read-through breaching into downstream repressed stage-specific genes, in the absence of either CPSF4 or the m6A RNA methylase components in bothT. gondiiandA. thaliana. Taken together, our results shed light on an essential regulatory mechanism coupling the pathways of m6A metabolism directly to the cleavage and polyadenylation processes, one that interestingly seem to serve, in bothT. gondiiandA. thaliana, as a guardian against aberrant transcriptional read-throughs.Highlightsm6A is recognized in apicomplexan and plants by CPSF4, a member of the cleavage and polyadenylation complex machinery.The structural insight behind the specificity of the binding of m6A by the CPSF4 YTH subunit are solved by high resolution crystal structures.The m6A-driven 3’end polyadenylation pathway protects transcriptome integrity by restricting transcriptional read-throughs and RNA chimera formation in apicomplexan parasites and plants.

Published
2021

3. A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment

Author

Yohann Couté, Dominique Cannella, Christopher Swale, Philippe Ortet, Fabien Sindikubwabo, Céline Dard, Lucid Belmudes, Alexandre Bougdour, Mohamed-Ali Hakimi, Mohamed Barakat, Dayana C. Farhat, Pieter-Jan De Bock, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire de parasitologie-mycologie, CHU Grenoble, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire d'Ecologie Microbienne de la Rhizosphère et d'Environnements Extrêmes (LEMIRE), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), 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)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-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)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-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), and ANR-18-CE15-0023,HostQuest,Stratégies de Persistence de Toxoplasma gondii : Conquérir la Cellule Hôte et Echapper à la Réponse Immune Innée(2018)

Subjects
Models, Molecular, Transcription, Genetic, [SDV]Life Sciences [q-bio], Protozoan Proteins, Antibodies, Protozoan, Applied Microbiology and Biotechnology, Protein Structure, Secondary, chromatin remodeling, Histones, microrchidia protein, Histone code, ComputingMilieux_MISCELLANEOUS, Adenosine Triphosphatases, Genetics, 0303 health sciences, Chromatin, Histone Code, Histone, Toxoplasma, epigenetic, Toxoplasmosis, Protein Binding, Microbiology (medical), Apetala 2, Primary Cell Culture, Immunology, Toxoplasma gondii, Biology, Microbiology, Histone Deacetylases, Article, 03 medical and health sciences, Animals, Humans, Epigenetics, Transcription factor, Gene, 030304 developmental biology, Life Cycle Stages, 030306 microbiology, Cell Biology, Fibroblasts, Cats, biology.protein, gene expression, sexual commitment, Histone deacetylase, Protein Processing, Post-Translational, Transcription Factors
Abstract

Toxoplasma gondii has a complex life cycle that is typified by asexual development that takes place in vertebrates, and sexual reproduction, which occurs exclusively in felids and is therefore less studied. The developmental transitions rely on changes in the patterns of gene expression, and recent studies have assigned roles for chromatin shapers, including histone modifications, in establishing specific epigenetic programs for each given stage. Here, we identified the T. gondii microrchidia (MORC) protein as an upstream transcriptional repressor of sexual commitment. MORC, in a complex with Apetala 2 (AP2) transcription factors, was shown to recruit the histone deacetylase HDAC3, thereby impeding the accessibility of chromatin at the genes that are exclusively expressed during sexual stages. We found that MORC-depleted cells underwent marked transcriptional changes, resulting in the expression of a specific repertoire of genes, and revealing a shift from asexual proliferation to sexual differentiation. MORC acts as a master regulator that directs the hierarchical expression of secondary AP2 transcription factors, and these transcription factors potentially contribute to the unidirectionality of the life cycle. Thus, MORC plays a cardinal role in the T. gondii life cycle, and its conditional depletion offers a method to study the sexual development of the parasite in vitro, and is proposed as an alternative to the requirement of T. gondii infections in cats.

Published
2020

4. A plant-like mechanism coupling m6A reading to polyadenylation safeguards transcriptome integrity and developmental gene partitioning in Toxoplasma

Author

Lucid Belmudes, Guillaume Communie, Dayana C. Farhat, Thierry Lagrange, Alexandre Bougdour, Dominique Pontier, Yohann Couté, Matthew W. Bowler, Charlotte Corrao, Christopher Swale, Mohamed-Ali Hakimi, Caroline Mas, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire européen de biologie moléculaire - European Molecular Biology Laboratory (EMBL Grenoble), European Molecular Biology Laboratory [Grenoble] (EMBL), Institut Laue-Langevin (ILL), ILL, Laboratoire Génome et développement des plantes (LGDP), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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)-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)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Integrated Structural Biology Grenoble (ISBG - UMS 3518 ), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-10-INSB-0801 ProFI ANR-10-INSB-0801, ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), ANR-18-CE15-0023,HostQuest,Stratégies de Persistence de Toxoplasma gondii : Conquérir la Cellule Hôte et Echapper à la Réponse Immune Innée(2018), ANR-10-LABX-0041,TULIP,Towards a Unified theory of biotic Interactions: the roLe of environmental(2010), ANR-18-EURE-0019,TULIP-GSR,The Toulouse-Perpignan(2018), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Integrated Structural Biology Grenoble (ISBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Rosalie, Martin, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Stratégies de Persistence de Toxoplasma gondii : Conquérir la Cellule Hôte et Echapper à la Réponse Immune Innée - - HostQuest2018 - ANR-18-CE15-0023 - AAPG2018 - VALID, Towards a Unified theory of biotic Interactions: the roLe of environmental - - TULIP2010 - ANR-10-LABX-0041 - LABX - VALID, and The Toulouse-Perpignan - - TULIP-GSR2018 - ANR-18-EURE-0019 - EURE - VALID

Subjects
Models, Molecular, Polyadenylation, Arabidopsis thaliana, Arabidopsis, Transcriptome, 0302 clinical medicine, Gene expression, Biology (General), 0303 health sciences, Microbiology and Infectious Disease, Membrane Glycoproteins, biology, General Neuroscience, Cleavage And Polyadenylation Specificity Factor, Zinc Fingers, General Medicine, Phenotype, epitranscriptomic, Cell biology, EPITRANSCRIPTOMIC MODIFICATIONS, Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA Splicing Factors, Toxoplasma, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Research Article, QH301-705.5, Science, Toxoplasma gondii, Nerve Tissue Proteins, M6A, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Genes, Developmental, RNA, Messenger, YTH DOMAIN, Gene, 030304 developmental biology, Binding Sites, General Immunology and Microbiology, Sequence Analysis, RNA, RNA, Methyltransferases, biology.organism_classification, RNA processing, Gene Expression Regulation, Reading, Other, 030217 neurology & neurosurgery
Abstract

Correct 3’end processing of mRNAs is one of the regulatory cornerstones of gene expression. In a parasite that must adapt to the regulatory requirements of its multi-host life style, there is a need to adopt additional means to partition the distinct transcriptional signatures of the closely and tandemly arranged stage-specific genes. In this study, we report our findings in T. gondii of an m6A-dependent 3’end polyadenylation serving as a transcriptional barrier at these loci. We identify the core polyadenylation complex within T. gondii and establish CPSF4 as a reader for m6A-modified mRNAs, via a YTH domain within its C-terminus, a feature which is shared with plants. We bring evidence of the specificity of this interaction both biochemically, and by determining the crystal structure at high resolution of the T. gondii CPSF4-YTH in complex with an m6A-modified RNA. We show that the loss of m6A, both at the level of its deposition or its recognition is associated with an increase in aberrantly elongated chimeric mRNAs emanating from impaired transcriptional termination, a phenotype previously noticed in the plant model Arabidopsis thaliana. Nanopore direct RNA sequencing shows the occurrence of transcriptional read-through breaching into downstream repressed stage-specific genes, in the absence of either CPSF4 or the m6A RNA methylase components in both T. gondii and A. thaliana. Taken together, our results shed light on an essential regulatory mechanism coupling the pathways of m6A metabolism directly to the cleavage and polyadenylation processes, one that interestingly seem to serve, in both T. gondii and A. thaliana, as a guardian against aberrant transcriptional read-throughs.

Published
2021

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