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dc.contributor.author
Shi, Xi
dc.contributor.author
Lu, Congyi
dc.contributor.author
Corman, Alba
dc.contributor.author
Nikish, Alexandra
dc.contributor.author
Zhou, Yang
dc.contributor.author
Platt, Randall
dc.contributor.author
Iossifov, Ivan
dc.contributor.author
Zhang, Feng
dc.contributor.author
Pan, Jen Q.
dc.contributor.author
Sanjana, Neville E.
dc.date.accessioned
2023-10-20T09:24:17Z
dc.date.available
2023-10-18T01:35:11Z
dc.date.available
2023-10-20T09:24:17Z
dc.date.issued
2023-10-05
dc.identifier.issn
0002-9297
dc.identifier.issn
1537-6605
dc.identifier.other
10.1016/j.ajhg.2023.09.004
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/637206
dc.description.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.
en_US
dc.language.iso
en
en_US
dc.publisher
Cell Press
en_US
dc.subject
autism
en_US
dc.subject
ASD
en_US
dc.subject
CHD8
en_US
dc.subject
chromodomain
en_US
dc.subject
Helicase
en_US
dc.subject
neurodevelopment
en_US
dc.subject
CRISPR
en_US
dc.subject
isogenic
en_US
dc.subject
chromatin
en_US
dc.subject
synaptic transmission
en_US
dc.title
Heterozygous deletion of the autism-associated gene CHD8 impairs synaptic function through widespread changes in gene expression and chromatin compaction
en_US
dc.type
Journal Article
dc.date.published
2023-10-05
ethz.journal.title
American Journal of Human Genetics
ethz.journal.volume
110
en_US
ethz.journal.issue
10
en_US
ethz.journal.abbreviated
Am J Hum Genet
ethz.pages.start
1750
en_US
ethz.pages.end
1768
en_US
ethz.size
19 p.
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
New York, NY
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2023-10-18T01:35:12Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2023-10-20T09:24:18Z
ethz.rosetta.lastUpdated
2024-02-03T05:27:18Z
ethz.rosetta.versionExported
true
ethz.COinS
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