CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells.
Ping Wang, Ryan Mokhtari, Erika Pedrosa and 4 others
PMID 28321286WHAT IT FOUND
Reducing one copy of the autism-linked CHD8 gene in lab-grown brain tissue disrupted genes controlling brain development and Wnt signaling.
These molecular changes matched those seen in autism and bipolar disorder samples, suggesting shared biological pathways rather than distinct diseases.
Key findings
01Heterozygous knockout of CHD8 in cerebral organoids resulted in 559 differentially expressed genes, with significant enrichment in pathways for nervous system development, neurogenesis, and Wnt/β-catenin signaling.
02The top differentially expressed gene, the non-coding RNA DLX6-AS1, was also the top differentially expressed gene in organoids derived from patients with idiopathic autism, indicating molecular convergence.
03CHD8 haploinsufficiency led to a substantial increase in TCF4 expression, a transcription factor implicated in schizophrenia and bipolar disorder, confirming a regulatory link between these genetic risk factors.
STILL TO COME
How it was doneWhat they found
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What it does not show
The study used iPS cells from a single control subject, meaning the findings may not generalize to other genetic backgrounds. The results are based on lab-grown brain tissue (organoids) and do not report any clinical outcomes or patient data. Cerebral organoids mimic first-trimester brain development, so they cannot model later stages of brain maturation or complex behaviors. The mechanism behind the discrepancy between CHD8 mRNA and protein levels remains unknown.
Declared interests
Funded by the National Institute of Mental Health. No other conflicts of interest are declared.
The easy way to misread this
Do not interpret these molecular findings as evidence that CHD8 mutations cause autism or bipolar disorder in a way that can be treated clinically today. This is a laboratory study of gene expression in brain-like tissue structures, not a trial of any therapy or diagnostic tool.