Major gains have been in made in mapping the genetic causes of neurodevelopmental disorders (NDDs). In autism spectrum disorder (ASD) and intellectual disability (ID), de novo mutations to a convergent network of genes encoding chromatin remodeling factors (CRFs) has emerged as one of the strongest components of genetic risk. A major challenge now facing the field is identifying the genomic mechanisms and neurodevelopmental consequences associated with mutations of NDD-associated CRFs. The CRF gene CHD8 has among the highest rates of de novo loss-of-function mutations observed in ASD and ID cohorts with mutations also described in schizophrenia and obsessive compulsive disorder cases, and CHD8 mutation carriers frequently also are diagnosed with macrocephaly. Our work and the work of others have confirmed that Chd8 germline heterozygous mutation in mice causes NDD-relevant pathological changes across genomic, neuroanatomical, and behavioral domains. Network analyses have linked functionality of CHD8 and other NDD-associated CRFs in the developing brain, raising the possibility that understanding CHD8- associated pathological mechanisms during neurodevelopment will reveal generalizable causal pathways mediated by CRF haploinsufficiency. However, independent of a role in early brain development, CHD8, as well as other NDD-associated CRFs, are expressed in neurons and mutation may drive behavioral pathology via neuron-specific impacts in postnatal brain. Thus, resolving developmental versus neuronal causality is essential for understanding CRF-associated mechanisms of NDDs. We will leverage conditional Chd8+/- mice model to dissect in vivo the mechanisms by which Chd8 mutations cause NDD-associated pathology. Our preliminary data suggests that macrocephaly and cognitive deficits are interdependent on pathology during early brain development in Chd8+/- mice, and that the molecular mechanisms are associated with chromatin-associated RNA processing mediated by Chd8. We will apply complementary -omics, cellular assays, and mouse studies to test this model, specifically, we will: 1) establish the mechanisms through which Chd8 haploinsufficiency impacts chromatin and transcription in embryonic brain, 2) characterize cell-type specific impacts of Chd8 haploinsufficiency on neurogenesis during brain development, and 3) define behavioral, EEG, and synaptic pathology caused by Chd8 haploinsufficiency and test whether such pathology is driven via developmental versus neuronal mechanism. This research will map the effect of Chd8 haploinsufficiency in vivo, illuminating mechanisms via which CHD8 dosage-sensitivity contributes to NDD pathology and linking molecular and cellular mechanisms to behavioral and systems level. Importantly, these critical studies cannot be done using in vitro models and such studies of high interest NDD risk genes is necessary to bridge genetic association and mechanistic understanding. By revealing causality for top risk genes such as CHD8, we will establish causal factors and identify novel treatments to improve care of NDDs.
Human genetic studies have revealed a surprising link between epigenetic regulators and psychiatric disorders, such as autism, schizophrenia, and intellectual disability. Identifying mechanisms underlying this link is critical to glean a picture of pathogenesis and neurobiology of these common, complex, and often- devastating brain disorders. Here, we will characterize the impacts of mutation to CHD8, one of the highest priority NDD risk genes discovered via case genome sequencing, on brain development and neuronal function. This work will contribute towards an ultimate goal of understanding core causal factors in complex brain disorders and ultimately using this understanding to better treat affected individuals.
