Single-Cell Transcriptomics Supports a Role of CHD8 in Autism

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.

How can same-gene mutations promote both cancer and developmental disorders?

“…Cohesin, a chromosome-associated multi-subunit protein complex ( 99 ), is another, possibly due to chromatin association. Chromatin regulators appear to be among the most frequently mutated genes in individuals with autism, and single-cell transcriptomics supports a role of CHD8, a DNA helicase that acts as a chromatin remodeling factor and regulates transcription in autism ( 100 , 101 ). Genome-wide analyses pointed to candidate genes encoding nuclear factors implicated in chromatin remodeling.…”

Context-dependant enhancers as a reservoir of functional polymorphisms and epigenetic markers linked to alcohol use disorders and comorbidities

“…Instead, we are in for a “long haul” where identifying functional enhancers, characterising the mechanisms regulating their context-dependency, and how they can be affected by genetic and environmental changes, necessitates the continued use of genetic manipulation of whole animal models such as zebrafish and mouse. But, thanks to our ability to rapidly engineer the genomes of vertebrate models such as mice and the rapid development of single cell sequencing technologies [85] , we are in a much better position to develop a greater understanding of the role of context-dependant enhancers in normal development and health than we were even ten years ago.…”

A Subphenotype-to-Genotype Approach Reveals Disproportionate Megalencephaly Autism Risk Genes

“…(which was not certified by peer review) preprint database (Figure 2) 25,44 . This analysis uncovered ontology groups enriched in our dataset previously reported for ASD, including proteins involved in histone modification and chromatin organization, transcription factors, cell signaling (e.g., SMAD and E-box binding), functions key to neuronal activity (e.g., sodium and calcium ion transport and glutamate receptor binding), cell adhesion and cytoskeletal proteins, and mRNA binding (Supplementary Table 3) [45][46][47][48] . Out of our original ASD-DM candidate seed genes 41.5% (69/166) fall under one of these ontologies.…”