Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes Academic Article uri icon

Overview

MeSH Major

  • Brain
  • Microglia
  • Quantum Dots

abstract

  • Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.

publication date

  • August 2019

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC6677164

Digital Object Identifier (DOI)

  • 10.1038/s41588-019-0472-1

PubMed ID

  • 31367015

Additional Document Info

start page

  • 1252

end page

  • 1262

volume

  • 51

number

  • 8