Traduction: G.M.
Proc Natl Acad Sci U S A. 2014 Oct 7. pii: 201405266. [Epub ahead of print]
CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors
Sugathan A1, Biagioli M2, Golzio C3, Erdin S4, Blumenthal I4, Manavalan P5, Ragavendran A4, Brand H1, Lucente D5, Miles J6, Sheridan SD1, Stortchevoi A4, Kellis M7, Haggarty SJ8, Katsanis N9, Gusella JF10, Talkowski ME11.
Author information
- 1Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Neurology and.
- 2Molecular Neurogenetics Unit and Departments of Neurology and.
- 3Center for Human Disease Modeling and.
- 4Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114;
- 5Molecular Neurogenetics Unit and.
- 6Departments of Pediatrics, Medical Genetics, and Pathology, The Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri Hospitals and Clinics, Columbia, MO 65201;
- 7Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139; and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142.
- 8Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Neurology and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142.
- 9Center for Human Disease Modeling and Department of Cell Biology, Duke University, Durham, NC 27710;
- 10Molecular Neurogenetics Unit and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142 Genetics, Harvard Medical School, Boston, MA 02115;
- 11Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Neurology and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142 talkowski@chgr.mgh.harvard.edu.
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.
Les mutations tronquées de la chromodomaine hélicase DNA-binding protéine 8 (CHD8), et de nombreux autres gènes avec des fonctions diverses, sont des facteurs à fort effet de risque de troubles du spectre autistique (TSA), suggérant de multiples mécanismes de la pathogenèse.
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.
Ces données indiquent que la perturbation hétérozygote de CHD8 précipite un réseau de changements d'expression des gènes impliqués dans les voies du développement neurologique dans laquelle de nombreux gènes associés au TSA peuvent converger sur les mécanismes communs de la pathogenèse.
Les mutations tronquées de la chromodomaine hélicase DNA-binding protéine 8 (CHD8), et de nombreux autres gènes avec des fonctions diverses, sont des facteurs à fort effet de risque de troubles du spectre autistique (TSA), suggérant de multiples mécanismes de la pathogenèse.
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.
Ces données indiquent que la perturbation hétérozygote de CHD8 précipite un réseau de changements d'expression des gènes impliqués dans les voies du développement neurologique dans laquelle de nombreux gènes associés au TSA peuvent converger sur les mécanismes communs de la pathogenèse.
- PMID: 25294932
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