GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis
| العنوان: | GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis |
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| المؤلفون: | Timothée Bigot, Marie Loosveld, Noémie Saut, Paul Saultier, Céline Falaise, Pierre-Emmanuel Morange, Sandrine Cabantous, Franck Peiretti, Johannes van Agthoven, Jean-Claude Bordet, Denis Bernot, Delphine Potier, Dominique Payet-Bornet, Matthias Canault, Michel Pucéat, Marie-Christine Alessi, Marjorie Poggi |
| المساهمون: | Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), AUTRES, Massachusetts General Hospital [Boston], Harward Medical School, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), DUMENIL, Anita |
| المصدر: | Journal of Thrombosis and Haemostasis Journal of Thrombosis and Haemostasis, 2021, 19 (9), pp.2287-2301. ⟨10.1111/jth.15412⟩ Journal of Thrombosis and Haemostasis, Wiley, 2021, 19 (9), pp.2287-2301. ⟨10.1111/jth.15412⟩ |
| بيانات النشر: | HAL CCSD, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Blood Platelets, [SDV]Life Sciences [q-bio], MYH10, Biology, Thrombopoiesis, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), GATA1, Gene expression, Gene silencing, Humans, GATA1 Transcription Factor, Gene Silencing, Transcription factor, Gene, 030304 developmental biology, Zinc finger, Genetics, 0303 health sciences, Nonmuscle Myosin Type IIB, Myosin Heavy Chains, Intron, Hematology, Thrombocytopenia, 3. Good health, [SDV] Life Sciences [q-bio], functional variants, platelets, downstream targets, Megakaryocytes, 030215 immunology, Transcription Factors |
| الوصف: | International audience; BackgroundGATA1 is an essential transcription factor for both polyploidization and megakaryocyte (MK) differentiation. The polyploidization defect observed in GATA1 variant carriers is not well understood.ObjectiveTo extensively phenotype two pedigrees displaying different variants in the GATA1 gene and determine if GATA1 controls MYH10 expression levels, a key modulator of MK polyploidization.MethodA total of 146 unrelated propositi with constitutional thrombocytopenia were screened on a multigene panel. We described the genotype-phenotype correlation in GATA1 variant carriers and investigated the effect of these novel variants on MYH10 transcription using luciferase constructs.ResultsThe clinical profile associated with the p.L268M variant localized in the C terminal zinc finger was unusual in that the patient displayed bleeding and severe platelet aggregation defects without early-onset thrombocytopenia. p.N206I localized in the N terminal zinc finger was associated, on the other hand, with severe thrombocytopenia (15G/L) in early life. High MYH10 levels were evidenced in platelets of GATA1 variant carriers. Analysis of MKs anti-GATA1 chromatin immunoprecipitation-sequencing data revealed two GATA1 binding sites, located in the 3′ untranslated region and in intron 8 of the MYH10 gene. Luciferase reporter assays showed their respective role in the regulation of MYH10 gene expression. Both GATA1 variants significantly alter intron 8 driven MYH10 transcription.ConclusionThe discovery of an association between MYH10 and GATA1 is a novel one. Overall, this study suggests that impaired MYH10 silencing via an intronic regulatory element is the most likely cause of GATA1-related polyploidization defect. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1538-7933 1538-7836 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::634bb6b82ec2348af9f619f47d61b6aaTest https://hal-amu.archives-ouvertes.fr/hal-03374701Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....634bb6b82ec2348af9f619f47d61b6aa |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387933 15387836 |
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