Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired verbal and non-verbal communication and is estimated to affect 21.7 million people worldwide. 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, large-scale exome sequencing studies of ASD patients 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. One such chromatin remodeler, chromodomain helicase DNA binding protein 8 (CHD8), is associated with 12 independent de novo loss-of- function mutations, which is the largest number of mutations in a single gene identified in individuals with ASD. CHD8 is an ATP-dependent chromatin-remodeling enzyme that regulates transcription, replication, repair, and recombination of the eukaryotic genome. Most ATP-dependent chromatin remodeling factors function within larger multi-subunit complexes, and previous studies from our lab have indicated that monomeric CHD8 (~290 kDa) participates in a larger complex of approximately 1 MDa. The long-term objective of this proposal is to determine the constitutive members of the complex and analyze how the tight association of CHD8 with other polypeptides may contribute to the role of the complex in the molecular pathology of ASD. We performed an affinity purification/mass spectrometry-based analysis of the endogenous CHD8 complex in the adult mouse cortex and identified several subunit candidates. One of the most promising hits is alpha thalassemia/mental retardation syndrome X-linked (ATRX), a protein previously shown to be involved in intellectual disability. In this proposal, we hypothesize that characterizing the relationship between CHD8 and ATRX through biochemical investigations and functional analyses will elucidate the role of the complex in ASD pathology.
The aims proposed here represent a novel and significant contribution to ASD research by shifting focus from transient partners of CHD8 to constituent members of the CHD8 complex, such as ATRX. From biochemical and structural characterization experiments, we expect ATRX to be a dedicated subunit of the complex and stably interact with CHD8. We anticipate understanding the functional roles that CHD8 and ATRX play in the complex by using neural progenitor cells. Through a mass spectrometric analysis of the embryonic CHD8 complex, we expect to discover the dedicated subunits and determine how the complex changes from the embryonic to adult stages of development. The connection uncovered between CHD8 and other proteins with contributions to neurodevelopmental diseases promises to provide a deeper understanding of pathological mechanisms and the identification of treatment targets for ASD individuals.
Autism spectrum disorder (ASD), characterized by impaired social and verbal development, is a common neurodevelopmental condition diagnosed in approximately 1 out of 68 children in the United States. Currently, mutations in several chromatin regulators have been causally linked to human neurodevelopmental and psychiatric disorders. The research proposed here promises to have considerable value in the pursuit of a deeper understanding of pathophysiological mechanisms and in the identification of treatment targets for ASD individuals.
|Platt, Randall J; Zhou, Yang; Slaymaker, Ian M et al. (2017) Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits. Cell Rep 19:335-350|