PUBLICATION
CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors
- Authors
- Sugathan, A., Biagioli, M., Golzio, C., Erdin, S., Blumenthal, I., Manavalan, P., Ragavendran, A., Brand, H., Lucente, D., Miles, J., Sheridan, S.D., Stortchevoi, A., Kellis, M., Haggarty, S.J., Katsanis, N., Gusella, J.F., Talkowski, M.E.
- ID
- ZDB-PUB-141009-2
- Date
- 2014
- Source
- Proceedings of the National Academy of Sciences of the United States of America 111(42): E4468-77 (Journal)
- Registered Authors
- Katsanis, Nicholas
- Keywords
- CHD8, ChIP-seq, NPCs, RNA-seq, autism
- MeSH Terms
-
- Animals
- Axons/metabolism
- Binding Sites
- Child Development Disorders, Pervasive/genetics*
- Child Development Disorders, Pervasive/metabolism
- Chromatin/metabolism
- DNA Helicases/metabolism
- DNA-Binding Proteins/genetics*
- DNA-Binding Proteins/physiology*
- Gene Expression Profiling
- Gene Expression Regulation, Developmental*
- Gene Expression Regulation, Neoplastic
- Gene Regulatory Networks
- Genome
- Heterozygote
- Humans
- Megalencephaly/metabolism
- Mutation
- Neoplasms/metabolism
- Neural Stem Cells/physiology*
- Neurons/metabolism
- Protein Binding
- Risk Factors
- Sequence Analysis, RNA
- Software
- Transcription Factors/genetics*
- Transcription Factors/physiology*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/physiology*
- PubMed
- 25294932 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Sugathan, A., Biagioli, M., Golzio, C., Erdin, S., Blumenthal, I., Manavalan, P., Ragavendran, A., Brand, H., Lucente, D., Miles, J., Sheridan, S.D., Stortchevoi, A., Kellis, M., Haggarty, S.J., Katsanis, N., Gusella, J.F., Talkowski, M.E. (2014) CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proceedings of the National Academy of Sciences of the United States of America. 111(42):E4468-77.
Abstract
Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping