Heterozygous deletion of the autism-associated gene CHD8 impairs synaptic function through widespread changes in gene expression and chromatin compaction

Xi Shi; Congyi Lu; Alba Corman; Alexandra Nikish; Yang Zhou; Randy J Platt; Ivan Iossifov; Feng Zhang; Jen Q Pan; Neville E Sanjana

doi:10.1016/j.ajhg.2023.09.004

Heterozygous deletion of the autism-associated gene CHD8 impairs synaptic function through widespread changes in gene expression and chromatin compaction

Am J Hum Genet. 2023 Oct 5;110(10):1750-1768. doi: 10.1016/j.ajhg.2023.09.004.

Authors

Xi Shi¹, Congyi Lu², Alba Corman², Alexandra Nikish³, Yang Zhou⁴, Randy J Platt⁵, Ivan Iossifov⁶, Feng Zhang³, Jen Q Pan⁷, Neville E Sanjana⁸

Affiliations

¹ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Bioengineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
² New York Genome Center, New York, NY, USA; Department of Biology, New York University, New York, NY, USA.
³ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Bioengineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute, Cambridge, MA, USA.
⁴ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Montreal Neurological Institute, Montreal, QC, Canada.
⁵ Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
⁶ New York Genome Center, New York, NY, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
⁷ Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. Electronic address: jpan@broadinstitute.org.
⁸ New York Genome Center, New York, NY, USA; Department of Biology, New York University, New York, NY, USA. Electronic address: neville@sanjanalab.org.

Abstract

Whole-exome sequencing of autism spectrum disorder (ASD) probands and unaffected family members has identified many genes harboring de novo variants suspected to play a causal role in the disorder. Of these, chromodomain helicase DNA-binding protein 8 (CHD8) is the most recurrently mutated. Despite the prevalence of CHD8 mutations, we have little insight into how CHD8 loss affects genome organization or the functional consequences of these molecular alterations in neurons. Here, we engineered two isogenic human embryonic stem cell lines with CHD8 loss-of-function mutations and characterized differences in differentiated human cortical neurons. We identified hundreds of genes with altered expression, including many involved in neural development and excitatory synaptic transmission. Field recordings and single-cell electrophysiology revealed a 3-fold decrease in firing rates and synaptic activity in CHD8^+/- neurons, as well as a similar firing-rate deficit in primary cortical neurons from Chd8^+/- mice. These alterations in neuron and synapse function can be reversed by CHD8 overexpression. Moreover, CHD8^+/- neurons displayed a large increase in open chromatin across the genome, where the greatest change in compaction was near autism susceptibility candidate 2 (AUTS2), which encodes a transcriptional regulator implicated in ASD. Genes with changes in chromatin accessibility and expression in CHD8^+/- neurons have significant overlap with genes mutated in probands for ASD, intellectual disability, and schizophrenia but not with genes mutated in healthy controls or other disease cohorts. Overall, this study characterizes key molecular alterations in genome structure and expression in CHD8^+/- neurons and links these changes to impaired neuronal and synaptic function.

Keywords: ASD; CHD8; CRISPR; autism; chromatin; chromodomain; helicase; isogenic; neurodevelopment; synaptic transmission.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autism Spectrum Disorder* / genetics
Autistic Disorder* / genetics
Chromatin / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Gene Expression
Humans
Mice
Transcription Factors / genetics

Substances

Chromatin
DNA-Binding Proteins
CHD8 protein, human
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding