33 - LANDSCAPE OF ALLELE-SPECIFIC OPEN CHROMATIN IN HUMAN IPSC-DIFFERENTIATED NEURONS AND IT IMPLICATION FOR MENTAL DISORDERS

Abstract

Background Allelic Imbalance of gene Expression (AIE) plays important role during neurodevelopment. However, the underlying mechanism of AIE has not been fully understood. Since chromatin accessibility (openness) has a strong influence on gene transcription, we hypothesised that allele-specific open chromatin (ASoC) might regulate AIE. Also, as open chromatin regions (OCRs) overlap with gene regulatory sequences and a genetic variant showing ASoC likely affects gene expression, we reasoned that mapping ASoC in neurons will help functionally interpret the abundant noncoding risk variants of neurodevelopmental disorders. Methods Using neurons derived from human induced pluripotent stem cells (iPSCs) as a cellular model, we carried out a global OCR profiling by Assay for Transposase-Accessible Chromatin through sequencing (ATAC-seq) and a transcriptomic profiling by RNA-seq in the same cell populations of different differentiation stages. We then identified all the heterozygous SNPs that show ASoC (in ATAC-seq data) or AIE (in RNA-seq data) by directly comparing the functional readouts (i.e, sequencing reads) of one allele vs. the other at heterozygous SNP sites within the same sample. Results We found that ASoC and AIE are both widespread and cell-type specific, and the differentiated neurons tend to have higher level of ASoC and AIE than in iPSCs. In iPSCs and neurons from the same human subject, out of the 10,048 heterozygous SNPs in OCRs, 101, 404, and 250 showed ASoC (P Discussion Our results not only provide novel insights into the epigenetic mechanisms of AIE during neural development but also suggest a new strategy for identifying functional noncoding disease risk variants that influence chromatin accessibility and gene expression in schizophrenia and other neurodevelopmental disorders.