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| Status |
Public on Oct 07, 2014 |
| Title |
CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors [ChIP-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Truncating mutations of CHD8, encoding a chromodomain helicase, 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-seq) with genome-wide CHD8 binding (ChIP-seq). Suppressing CHD8 to levels comparable with 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 = 1.01x10-9) and CHD8-bound genes (p = 4.34x10-3), which align with previously identified co-expression modules during fetal development. We also find an intriguing enrichment of cancer related gene-sets among CHD8-bound genes (p < 1.9x10-11). 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.
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| Overall design |
ChIP-seq for CHD8 using three different antibodies, and the related protein CHD7, in human iPSC-derived NPCs treated with shRNA targeting GFP (which were used as control cells for an shRNA knockdown RNA-seq experiment that was part of the overall study)
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| Contributor(s) |
Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, Sheridan SD, Stortchevoi A, Haggarty SJ, Katsanis N, Gusella JF, Talkowski ME |
| Citation(s) |
25294932 |
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| Submission date |
Sep 17, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Michael E Talkowski |
| E-mail(s) |
talkowski@chgr.mgh.harvard.edu
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| Organization name |
Massachusetts General Hospital
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| Street address |
185 Cambridge Street
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02114 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (5)
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| This SubSeries is part of SuperSeries: |
| GSE61492 |
CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors |
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| Relations |
| BioProject |
PRJNA261291 |
| SRA |
SRP047226 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE61487_CHD8all3_MACS2.bed.gz |
82.4 Kb |
(ftp)(http) |
BED |
| GSE61487_RAW.tar |
920.0 Kb |
(http)(custom) |
TAR (of BED) |
SRA Run Selector |
| Processed data are available on Series record |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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