MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts.
Cell Stem Cell
; 21(3): 332-348.e9, 2017 09 07.
Article
em En
| MEDLINE
| ID: mdl-28886366
Directed reprogramming of human fibroblasts into fully differentiated neurons requires massive changes in epigenetic and transcriptional states. Induction of a chromatin environment permissive for acquiring neuronal subtype identity is therefore a major barrier to fate conversion. Here we show that the brain-enriched miRNAs miR-9/9∗ and miR-124 (miR-9/9∗-124) trigger reconfiguration of chromatin accessibility, DNA methylation, and mRNA expression to induce a default neuronal state. miR-9/9∗-124-induced neurons (miNs) are functionally excitable and uncommitted toward specific subtypes but possess open chromatin at neuronal subtype-specific loci, suggesting that such identity can be imparted by additional lineage-specific transcription factors. Consistently, we show that ISL1 and LHX3 selectively drive conversion to a highly homogeneous population of human spinal cord motor neurons. This study shows that modular synergism between miRNAs and neuronal subtype-specific transcription factors can drive lineage-specific neuronal reprogramming, providing a general platform for high-efficiency generation of distinct subtypes of human neurons.
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Base de dados:
MEDLINE
Assunto principal:
Cromatina
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MicroRNAs
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Reprogramação Celular
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Fibroblastos
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Neurônios
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article