The objective of the proposed research is to translate genetic findings to potential prevention and treatment options for autism spectrum disorder (ASD). ASD is a highly prevalent neurodevelopmental disorder characterized by abnormal social communication and repetitive behaviors with restricted interests. The combination of lifelong social and behavioral challenges, along with a lack of therapeutic agents designed to treat core symptoms, places ASD as a significant priority in health care. Our functional analyses revealed that a genome wide significant ASD association peak on chromosome 5p14.1 implicated the long noncoding RNA MSNP1AS (moesin pseudogene 1, anti-sense; P=10-10 with ASD). Experiments performed during the first four years of this project revealed that MSNP1AS expression in human neural progenitor cells is highly responsive to exposure to air pollutants, environmental factors that have been independently associated with ASD risk. Experiments performed during the first four years of this project also revealed that over-expression of MSNP1AS in human neural progenitor cells regulates expression of chromodomain helicase DNA binding protein 8 (CHD8), a leading ASD candidate gene based on whole exome sequencing and subsequent targeted sequencing studies. In this renewal application, we provide preliminary evidence that 6 long noncoding RNAs, including MSNP1AS, act as functional links between environmental factors and genes associated with ASD by de novo loss-of-function mutations. We hypothesize that a common pathway links environmental, epigenetics and high impact rare mutations in a biological pathway that may contribute to a large fraction of ASD cases. Exposure of human neural progenitor cells to model air pollutants significantly increased the expression of ASD-related long noncoding RNAs (lncRNAs) and significantly decreased CHD8 expression. We published data indicating that siRNA-mediated knockdown of CHD8 in human neural progenitor cells followed by RNA- sequencing revealed that CHD8 insufficiency results in widespread transcriptional changes involving both protein-coding and noncoding RNAs. Unpublished data indicate that air pollutant exposure and siRNA- mediated CHD8 insufficiency lead to overlapping changes in gene expression, neural progenitor cell proliferation, and mature cortical projection neuron morphology. The proposed project aims to determine the mechanisms of environmental and epigenetic regulation of CHD8, with the ultimate goal of identifying translatable therapeutic intervention.
Aim 1 will determine the impact of air pollution exposure on gene expression, proliferation and morphology in human neural progenitor cells.
Aim 2 will rescue the phenotypes of air pollution exposure by transcriptional gene silencing of ASD-related lncRNAs in human neural progenitor cells.
Aim 3 will rescue the impact of air pollution exposure by transcriptional derepression of CHD8 in human neural progenitor cells. These data will identify convergent molecular pathways that link environmental, epigenetic, and genetic factors implicated in ASD for potential translatable intervention.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects ~1% of children. Recent studies indicate contributions of environmental factors, common genetic variants, and rare mutations to ASD risk. This research proposal will explore a convergent molecular pathway that links air pollution, long noncoding RNAs and a gene often mutated in individuals with ASD to identify potential molecular treatment targets.
