title: CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.
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.
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Neurology and.
authors.forename: Aarathi
authors.initials: A
authors.lastname: Sugathan
authors.affiliation: Molecular Neurogenetics Unit and Departments of Neurology and.
authors.forename: Marta
authors.initials: M
authors.lastname: Biagioli
authors.affiliation: Center for Human Disease Modeling and.
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Serkan
authors.initials: S
authors.lastname: Erdin
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Ian
authors.initials: I
authors.lastname: Blumenthal
authors.affiliation: Molecular Neurogenetics Unit and.
authors.forename: Poornima
authors.initials: P
authors.lastname: Manavalan
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Ashok
authors.initials: A
authors.lastname: Ragavendran
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Neurology and.
authors.forename: Harrison
authors.initials: H
authors.lastname: Brand
authors.affiliation: Molecular Neurogenetics Unit and.
authors.forename: Diane
authors.initials: D
authors.lastname: Lucente
authors.affiliation: Departments of Pediatrics, Medical Genetics, and Pathology, The Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri Hospitals and Clinics, Columbia, MO 65201;
authors.forename: Judith
authors.initials: J
authors.lastname: Miles
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Neurology and.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Sheridan
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Alexei
authors.initials: A
authors.lastname: Stortchevoi
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139; and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: Molecular 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.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.affiliation: Center for Human Disease Modeling and Department of Cell Biology, Duke University, Durham, NC 27710;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Molecular Neurogenetics Unit and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142 Genetics, Harvard Medical School, Boston, MA 02115;
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Molecular 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.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D001665:Binding Sites; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D016678:Genome; D006579:Heterozygote; D006801:Humans; D058627:Megalencephaly / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D012307:Risk Factors; D017423:Sequence Analysis, RNA; D012984:Software; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C523331:CHD8 protein, human; C000592497:CHD8 protein, zebrafish; D002843:Chromatin; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; D004265:DNA Helicases
keywords: CHD8; ChIP-seq; NPCs; RNA-seq; autism