Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes

Cell Rep. 2024 Jun 25;43(6):114329. doi: 10.1016/j.celrep.2024.114329. Epub 2024 Jun 7.

Abstract

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000 bp upstream of the transcription start site, was highly predictive of brain-expressed genes. This signature was observed in 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After 8 days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest that functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.

Keywords: CP: Genomics; CP: Neuroscience; CRISPRi; autism spectrum disorder; chromatin; convergence; genomics; haploinsufficient disorders; human fetal development; mouse brain development; transcriptional regulators.

MeSH terms

  • Animals
  • Autism Spectrum Disorder / genetics
  • Autism Spectrum Disorder / metabolism
  • Autism Spectrum Disorder / pathology
  • Autistic Disorder / genetics
  • Autistic Disorder / metabolism
  • Autistic Disorder / pathology
  • Brain* / metabolism
  • Gene Expression Regulation
  • Genetic Loci
  • Humans
  • Mice
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Transcription Factors