Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired verbaland non-verbal communication and is estimated to affect 21.7 million people worldwide. It is well establishedthat ASD has a strong genetic component with evidence of allelic and locus heterogeneity. Yet, the underlyinggenetic cause of ASD is unknown for at least 70% of cases. Recently, large-scale exome sequencing studiesof ASD patients have led to the discovery of candidate genes based on de novo loss-of-function mutations thatcarry large biological effects and high risk for ASD. Currently, mutations in several chromatin regulators havebeen 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, andrecombination of the eukaryotic genome. Most ATP-dependent chromatin remodeling factors function withinlarger multi-subunit complexes, and previous studies from our lab have indicated that monomeric CHD8 (~290kDa) participates in a larger complex of approximately 1 MDa. The long-term objective of this proposal is todetermine the constitutive members of the complex and analyze how the tight association of CHD8with 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 CHD8complex in the adult mouse cortex and identified several subunit candidates. One of the most promising hits isalpha thalassemia/mental retardation syndrome X-linked (ATRX), a protein previously shown to be involved inintellectual disability. In this proposal, we hypothesize that characterizing the relationship between CHD8and ATRX through biochemical investigations and functional analyses will elucidate the role of thecomplex in ASD pathology. The aims proposed here represent a novel and significant contribution to ASDresearch by shifting focus from transient partners of CHD8 to constituent members of the CHD8 complex, suchas ATRX. From biochemical and structural characterization experiments, we expect ATRX to be a dedicatedsubunit of the complex and stably interact with CHD8. We anticipate understanding the functional roles thatCHD8 and ATRX play in the complex by using neural progenitor cells. Through a mass spectrometric analysisof the embryonic CHD8 complex, we expect to discover the dedicated subunits and determine how thecomplex changes from the embryonic to adult stages of development. The connection uncovered betweenCHD8 and other proteins with contributions to neurodevelopmental diseases promises to provide a deeperunderstanding of pathological mechanisms and the identification of treatment targets for ASD individuals.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
