Epigenetic Control of High Confidence Autism Spectrum Disorder Genes

Project Description Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by social communication deficits and repetitive behaviors with restricted interests. The 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. There are four established risk factors for ASD. First, ASD is diagnosed four times more often in males than females, so male sex is an ASD risk factor. Second, exome sequencing studies of tens of thousands of individuals with ASD identified >200 high-confidence ASD genes with rare mutations. Prominent among these ASD high-confidence genes is chromodomain helicase DNA binding protein 8 (CHD8), which is strongly associated with ASD by de novo loss-of-function mutations. The exome sequencing data indicated that CHD8 insufficiency strongly predicts ASD diagnosis, so CHD8 loss-of-function mutations are an ASD risk factor. We and others published papers showing the downstream effects of CHD8 insufficiency in human neural progenitor cells. Third, epidemiologic studies provide strong evidence that the environmental factors valproic acid and air pollution fine particulate matter exposure contribute to ASD risk. We recently discovered that exposure of human cerebral organoids to either valproic acid or particulate matter results in decreased CHD8 expression. The finding that ASD-associated environmental factors can lead to the molecular endpoint of CHD8 insufficiency suggests a convergent biological pathway. Fourth, genome wide association studies (GWAS) have identified two replicated loci associated with ASD on chromosomes 5p14.1 and 20p12.1. We discovered and published that two long noncoding RNAs (lncRNAs) are among the functional elements revealed by the GWAS peaks. Each of these lncRNAs is expressed at higher levels in postmortem brains of individuals with ASD, is increased in expression following model air pollutant exposure, and causes decreased CHD8 expression when the lncRNA is over-expressed in human neural progenitor cells. Based on these convergent data indicating environmental and epigenetic control of the high-confidence ASD gene CHD8, we propose two aims. Aim 1 will test the responses to valproic acid and fine particulate matter of human cerebral organoids derived from individuals with mutations in CHD8, ASD risk genetic variants on chromosomes 5p14.1 and 20p12.1, and both sexes. Aim 2 will test the ability of lncRNA transcriptional gene silencing and CHD8 derepression to rescue the phenotypes of CHD8 insufficiency. The outcomes will include single cell gene expression, quantitative neuronal differentiation, and synaptic physiology. These studies will contribute to understanding the neurodevelopmental impacts of environmental exposures, CHD8 insufficiency, and environmental and epigenetic control of CHD8. We expect the research program will lead to biologically based treatment options for a subset of patients and provide a platform to study epigenetic control of additional genes that contribute to neurodevelopmental disorders. Project Number: 1R01ES036522-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Daniel Campbell | Institution: HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES, EAST LANSING, MI | Award Amount: $790,980 | Activity Code: R01 | Study Section: Genetics of Health and Disease Study Section[GHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11126981