Abnormal Chromatin Remodeling Caused by ARID1A Deletion Leads to Malformation of the Dentate Gyrus

Abstract

AbstractARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be a tumor suppressor. Recently, loss-of-function of ARID1A gene has been shown to cause intellectual disability. Here we generateArid1aconditional knockout mice and investigateArid1afunction in the hippocampus. Disruption ofArid1ain mouse forebrain significantly decreases neural stem/progenitor cells (NSPCs) proliferation and differentiation to neurons within the dentate gyrus (DG), increases perinatal and postnatal apoptosis, leading to reduced hippocampus size. Moreover, we perform single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and reveal thatArid1ais necessary for the maintenance of the DG progenitor pool and survival of post-mitotic neurons. Transcriptome and ChIP-seq analysis data demonstrate that ARID1A specifically regulatesProx1by altering the levels of histone modifications. Overexpression of downstream targetProx1can rescue proliferation and differentiation defects of NSPCs caused by Arid1a deletion. Overall, our results demonstrate a critical role forArid1ain the development of the hippocampus and may also provide insight into the genetic basis of intellectual disabilities such as Coffin–Siris syndrome, which is caused by germ-line mutations or microduplication ofArid1a.