Abstract
Chromodomain helicase domain 8 (CHD8) is one of the most frequently mutated and most penetrant genes in the autism spectrum disorder (ASD). Individuals with CHD8 mutations show leading symptoms of autism, macrocephaly, and facial dysmorphisms. The molecular and cellular mechanisms underpinning the early onset and development of these symptoms are still poorly understood and prevent timely and more efficient therapies of patients. Progress in this area will require an understanding of “when, why and how cells deviate from their normal trajectories”. High-throughput single-cell RNA sequencing (sc-RNAseq) directly quantifies information-bearing RNA molecules that enact each cell’s biological identity. Here, we discuss recent insights from sc-RNAseq of CRISPR/Cas9-editing of Chd8/CHD8 during mouse neocorticogenesis and human cerebral organoids. Given that the deregulation of the balance between excitation and inhibition (E/I balance) in cortical and subcortical circuits is thought to represent a major etiopathogenetic mechanism in ASD, we focus on the question of whether, and to what degree, results from current sc-RNAseq studies support this hypothesis. Beyond that, we discuss the pros and cons of these approaches and further steps to be taken to harvest the full potential of these transformative techniques.
Highlights
Chromodomain helicase domain 8 (CHD8) is one of the most frequently mutated and most penetrant genes in the autism spectrum disorder (ASD)
This study showed that germline Chd8 heterozygosity associates with sexpreponderant behavioral deficits and sexually dimorphic inhibitory synaptic transmission in the hippocampus, a brain region strongly connected to different brain regions involved in ASD
One-third of the individuals with a mutation in CHD8 present variable degrees of ventriculomegaly and delayed myelination [64]. These findings indicate that disruption of Chd8 during mid fetal neocorticogenesis in mice elicits postnatal perturbations in gene expression modules relevant to clinical phenotypes
Summary
Autism spectrum disorder (ASD) encompasses a spectrum of early-onset neurodevelopmental disorders with an estimated prevalence of ~1.5% in developed countries [1]. CRs regulate regulatenucleosome nucleosomesliding, sliding,conformational conformationalchanges changesof ofnucleosomal nucleosomalDNA, DNA,and and CRs exchange of of histone histone variants All these these processes processes affect affectthe theaccess accessof oftranscription transcriptionfactors factors exchange (TFs) to totheir theirbinding bindingsites, sites,and andconsequently, ,gene geneexpression expression(reviewed (reviewedin in[19]). ATPaseATPase domaindomain are important to chromatin binding, interaction with mains to the central are important to chromatin binding, interaction specific histone modifications, and/orand/or regulation of ATPase activity.activity In this regard, CHD8 with specific histone modifications, regulation of ATPase contains an N-terminal tandemtandem chromodomain mediating bindingbinding to methylated lysine. CHDs, including CHD8, recognize chromatin signatures that can undergo dynamic changes, modulating their regulatory space Such plasticity makes it more difficult to define genuine CHD target genes when compared to genes targeted by DNA sequence-specific TFs [12,14]
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