Lineage specific transcription factors and epigenetic regulators mediate TGFß-dependent enhancer activation.
Nucleic Acids Res
; 46(7): 3351-3365, 2018 04 20.
Article
en En
| MEDLINE
| ID: mdl-29438503
ABSTRACT
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 TGFß 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 TGFß-responsive Neurog2 enhancer is essential for proper neuronal polarization.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Factor de Crecimiento Transformador beta
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Elementos de Facilitación Genéticos
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Proteína smad3
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico
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Neurogénesis
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2018
Tipo del documento:
Article
País de afiliación:
España