CRISPR-Mediated Multiplexed Epigenomic Perturbation of Putatively Functional ASoC Sites in Human Neural Progenitor Cell Model at Single-cell Resolution

ABSTRACT: Functional interpretation of noncoding disease variants, which likely regulate gene expression, has been challenging. Chromatin accessibility (openness) strongly influences gene expression in neurodevelopment; however, to what extent genetic variants can alter chromatin openness in the context of brain disorders/traits is largely unknown. Using human induced pluripotent stem cell (iPSC)-derived neurons as a neurodevelopmental model, we identified abundant open-chromatin regions absent in brains and thousands of genetic variants exhibiting allele-specific open-chromatin (ASoC). ASoC variants are overrepresented in brain enhancers, transcription-factor-binding sites, and quantitative-trait-loci affecting histone modifications or DNA methylation. ASoC variants are also highly enriched for those associated with brain disorders/traits. Following-up schizophrenia-associated ASoC variants by multiplex epigenomic perturbation, computational fine-mapping, and CRISPR-editing further confirmed their regulatory activities and cis-targeted genes. Our study provides the first snapshot of neuronal ASoC landscape and a framework for prioritizing functional disease variants.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132757 | GEO | 2020/05/05

REPOSITORIES: GEO