Open Chromatin Profiling in hiPSC-Derived Neurons Prioritizes Functional Noncoding Psychiatric Risk Variants and Highlights Neurodevelopmental Loci.
Cell Stem Cell
; 21(3): 305-318.e8, 2017 09 07.
Article
em En
| MEDLINE
| ID: mdl-28803920
ABSTRACT
Most disease variants lie within noncoding genomic regions, making their functional interpretation challenging. Because chromatin openness strongly influences transcriptional activity, we hypothesized that cell-type-specific open chromatin regions (OCRs) might highlight disease-relevant noncoding sequences. To investigate, we mapped global OCRs in neurons differentiating from hiPSCs, a cellular model for studying neurodevelopmental disorders such as schizophrenia (SZ). We found that the OCRs are highly dynamic and can stratify GWAS-implicated SZ risk variants. Of the more than 3,500 SZ-associated variants analyzed, we prioritized â¼100 putatively functional ones located in neuronal OCRs, including rs1198588, at a leading risk locus flanking MIR137. Excitatory neurons derived from hiPSCs with CRISPR/Cas9-edited rs1198588 or a rare proximally located SZ risk variant showed altered MIR137 expression, dendrite arborization, and synapse maturation. Our study shows that noncoding disease variants in OCRs can affect neurodevelopment, and that analysis of open chromatin regions can help prioritize functionally relevant noncoding variants identified by GWAS.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esquizofrenia
/
Cromatina
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Predisposição Genética para Doença
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Células-Tronco Pluripotentes Induzidas
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Loci Gênicos
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Sistema Nervoso
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Neurônios
Tipo de estudo:
Etiology_studies
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Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Cell Stem Cell
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos