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Cell Stem Cell. 2017 Sep 7;21(3):305-318.e8. doi: 10.1016/j.stem.2017.07.008. Epub 2017 Aug 10.

Open Chromatin Profiling in hiPSC-Derived Neurons Prioritizes Functional Noncoding Psychiatric Risk Variants and Highlights Neurodevelopmental Loci.

Author information

1
Department of Physiology, Northwestern University, Chicago, IL 60611, USA.
2
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.
3
Department of Neuroscience and Cell Biology and Child Health Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA.
4
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
5
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA.
6
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
7
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
8
Department of Physiology, Northwestern University, Chicago, IL 60611, USA. Electronic address: p-penzes@northwestern.edu.
9
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA. Electronic address: jduan@uchicago.edu.

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 ∼100 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.

KEYWORDS:

ATAC-seq; CRISPR/Cas9; GWAS; MIR137; hiPSC; neurodevelopment; noncoding; open chromatin; schizophrenia; synapse

PMID:
28803920
PMCID:
PMC5591074
DOI:
10.1016/j.stem.2017.07.008
[Indexed for MEDLINE]
Free PMC Article

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