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Prdm6 controls heart development by regulating neural crest cell differentiation and migration.
Hong, Lingjuan; Li, Na; Gasque, Victor; Mehta, Sameet; Ye, Lupeng; Wu, Yinyu; Li, Jinyu; Gewies, Andreas; Ruland, Jürgen; Hirschi, Karen K; Eichmann, Anne; Hendry, Caroline; van Dijk, David; Mani, Arya.
Afiliación
  • Hong L; Cardiovascular Research Center, Department of Internal Medicine.
  • Li N; Cardiovascular Research Center, Department of Internal Medicine.
  • Gasque V; Cardiovascular Research Center, Department of Internal Medicine.
  • Mehta S; Yale Center for Genome Analysis, and.
  • Ye L; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
  • Wu Y; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
  • Li J; Cardiovascular Research Center, Department of Internal Medicine.
  • Gewies A; Helmholtz Zentrum München, Munich, Germany.
  • Ruland J; The Technical University of Munich, Munich, Germany.
  • Hirschi KK; Cardiovascular Research Center, Department of Internal Medicine.
  • Eichmann A; University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Hendry C; Cardiovascular Research Center, Department of Internal Medicine.
  • van Dijk D; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • Mani A; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
JCI Insight ; 7(4)2022 02 02.
Article en En | MEDLINE | ID: mdl-35108221
The molecular mechanisms that drive the acquisition of distinct neural crest cell (NCC) fates is still poorly understood. Here, we identified Prdm6 as an epigenetic modifier that temporally and spatially regulates the expression of NCC specifiers and determines the fate of a subset of migrating cardiac NCCs (CNCCs). Using transcriptomic analysis and genetic and fate mapping approaches in transgenic mice, we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction. Bulk and single-cell RNA-Seq analyses of the DA and CNCCs identified Prdm6 as a regulator of a network of CNCC specification genes, including Wnt1, Tfap2b, and Sox9. Loss of Prdm6 in CNCCs diminished its expression in the pre-epithelial-mesenchymal transition (pre-EMT) cluster, resulting in the retention of NCCs in the dorsal neural tube. This defect was associated with diminished H4K20 monomethylation and G1-S progression and augmented Wnt1 transcript levels in pre-EMT and neural tube clusters, which we showed was the major driver of the impaired CNCC migration. Altogether, these findings revealed Prdm6 as a key regulator of CNCC differentiation and migration and identified Prdm6 and its regulated network as potential targets for the treatment of congenital heart diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / ARN / Regulación del Desarrollo de la Expresión Génica / Organogénesis / Transición Epitelial-Mesenquimal / Cardiopatías Congénitas / Cresta Neural Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: JCI Insight Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / ARN / Regulación del Desarrollo de la Expresión Génica / Organogénesis / Transición Epitelial-Mesenquimal / Cardiopatías Congénitas / Cresta Neural Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: JCI Insight Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos