Genomic Characterization of CHD8 with Implications for Autism Spectrum Disorder.

다국어 초록 (Multilingual Abstract)

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by restricted social interaction, impaired verbal and non-verbal communication, and repetitive behavior. ASD is estimated to affect 24.8 million people worldwide and is diagnosed in about 1.7% of children in the United States. It is well established that ASD has a strong genetic component with evidence of allelic and locus heterogeneity. Yet, the underlying genetic cause of ASD is unknown for at least 70% of cases. Recently, largescale exome sequencing studies of ASD patients from unaffected parents have led to the discovery of candidate genes based on de novo loss-of-function mutations that carry large biological effects and high risk for ASD. Currently, mutations in several chromatin regulators have been causally linked to human neurodevelopmental and psychiatric disorders, such as ASD and schizophrenia. One such chromatin remodeler, chromodomain helicase DNA binding protein 8 (CHD8), is associated with 12 mutated alleles, consisting of nonsense mutations or frameshift insertions/deletions that confer a haploinsufficient phenotype. CHD8 has been established as one of the most frequently mutated genes in ASD.CHD8 is thought to use the energy of ATP hydrolysis to catalyze structural changes in chromatin, allowing transcription factors to access their cognate binding sites, replace histones with histone variants, and reposition nucleosomes on a DNA template to tightly control gene expression. CHD8, a member of the CHD6-9 subfamily of CHD chromatin remodelers, exhibits a diverse range of functions in transcriptional regulation. Ectopic expression studies have indicated that CHD8 suppresses p53-dependent activation and apoptosis. It has also been found to regulate the Wnt signaling pathway by repressing β- catenin target genes. Previous chromatin immunoprecipitation (ChIP) experiments have shown that CHD8 binds to the promoters of approximately 2000 active genes that are enriched for H3K4me2 and H3K4me3 marks. In addition, CHD8 has been shown to interact with CTCF, with members of the MLL1 transcription activation complex, and with elongating RNA Polymerase II (RNAPII). CHD7, which causes CHARGE syndrome, a condition characterized by abnormal development of the neural crest, has also been shown to interact with CHD8.This thesis covers a brief overview of where the field of autism is now, an in-depth analysis of the genomic characterization of CHD8 and the role that it plays during the early stages of neurogenesis, and characterization of a CHD8 haploinsufficient mouse model that is able to recapitulate some of the autism phenotypes in vivo.