Hemizygous deletion of the autism-associated gene CHD8 impairs synaptic function through widespread changes in gene expression and chromatin compaction (ATAC-Seq)

In this study, we developed two isogenic haploinsufficient CHD8+/– human embryonic stem cell lines (hESCs) that we induced into neurons (iNs) upon doxycycline-inducible overexpression of Neurogenin 2 and Neurogenin 1 (NEUROG2/1), and we profiled the key molecular alterations in chromatin accessibility (ATAC-seq) and expression (RNA-seq) resulting from the loss of CHD8, the most recurrently mutated gene in autism spectrum disorders (ASD). Overall design: We examined transcriptome profiles using RNA-seq and chromatin structure using ATAC-seq in 3 cell types, two clonal CHD8+/– hESCs HUES66 lines (CHD8-A and CHD8-B) and the isogenic control (H66), which were differentiated into neurons (iNs) after 9 days of doxycycline-inducible overexpression of Neurogenin 2 and Neurogenin 1 (NEUROG2/1) (Ngn, Day9). For the ATAC-seq characterization, two biological replicates of induced neurons (Ngn, Day9) for each line (H66, CHD8-A, and CHD8-B) were deeply sequenced and analyzed.