Lineage specific transcription factors and epigenetic regulators mediate TGFβ-dependent enhancer activation
| Autor: | Marian A. Martínez-Balbás, Conchi Estarás, Simona Iacobucci, Xavier de la Cruz, Raquel Fueyo, Marta Vicioso-Mantis, Sara Cruz-Molina, Alvaro Rada-Iglesias, Stella Pappa, José C. Reyes, Sergio Lois, Claudia Navarro |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Jérôme Lejeune Foundation, Company of Biologists, Ministerio de Educación y Ciencia (España) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Jumonji Domain-Containing Histone Demethylases Histone-modifying enzymes Neurogenesis Nerve Tissue Proteins Biology Epigenesis Genetic Mice 03 medical and health sciences Neural Stem Cells Transforming Growth Factor beta Transcription (biology) Basic Helix-Loop-Helix Transcription Factors Genetics Animals Cell Lineage Smad3 Protein Epigenetics Promoter Regions Genetic Enhancer Transcription factor Regulation of gene expression Gene regulation Chromatin and Epigenetics Cell Polarity Chromatin Cell biology DNA-Binding Proteins ASCL1 Enhancer Elements Genetic 030104 developmental biology CRISPR-Cas Systems Signal Transduction Transcription Factors |
| Zdroj: | Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) Digital.CSIC. Repositorio Institucional del CSIC instname Nucleic Acids Research |
| Popis: | © The Author(s) 2018. During neurogenesis, dynamic developmental cues, transcription factors and histone modifying enzymes regulate the gene expression programs by modulating the activity of neural-specific enhancers. How transient developmental signals coordinate transcription factor recruitment to enhancers and to which extent chromatin modifiers contribute to enhancer activity is starting to be uncovered. Here, we take advantage of neural stem cells as a model to unravel the mechanisms underlying neural enhancer activation in response to the TGFβ signaling. Genome-wide experiments demonstrate that the proneural factor ASCL1 assists SMAD3 in the binding to a subset of enhancers. Once located at the enhancers, SMAD3 recruits the histone demethylase JMJD3 and the remodeling factor CHD8, creating the appropriate chromatin landscape to allow enhancer transcription and posterior gene activation. Finally, to analyze the phenotypical traits owed to cis-regulatory regions, we use CRISPR–Cas9 technology to demonstrate that the TGFβ-responsive Neurog2 enhancer is essential for proper neuronal polarization. Spanish Ministry of Education and Science [BFU2015-69248-P, BFU20012-34261 to M.M.B.]; Fundaciò La Marató de TV3 [090210 to M.M.B.]; Jérôme Lejeune Fondation; FPU fellowship and a travelling fellowship from the Company of Biologists (to R.F.). Funding for open access charge: Spanish Ministry of Education and Science [BFU2015-69248]. |
| Databáze: | OpenAIRE |
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