Research Plan Abstract Chromatin structure controls the global and local transcriptional potential of the genome, enabling the diversification of eukaryotic cell types and function through finely-tuned gene expression patterns. Unlike DNA itself, chromatin is dynamic, enabling changes in functional readout of the genome based on the activity of chromatin remodeling factors (CRFs). Despite the central role of chromatin remodeling in guiding activation and repression of gene expression in the development and function of the mammalian brain, critical gaps remain in our understanding about the role of most CRFs. In the past decade, case sequencing studies have revealed the surprising finding that single copy loss-of-function mutations of numerous CRFs are major causal factors in neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), schizophrenia, and intellectual disability. Chromodomain helicase DNA binding protein 8 (CHD8) is a CRF with one of the highest observed de novo loss-of-function mutations rates in patients with ASD, with mutations also described in patients with schizophrenia and intellectual disability, making it a gene of high relevance. While genetic studies have made clear that haploinsufficiency of CRFs such as CHD8 represent a strong contributing factor in neurodevelopmental disorders, the mechanisms driving pathology in the embryonic and postnatal brain remain unknown. This lack of functional characterization represents a critical barrier to understanding the role of CRFs in normal and pathogenic processes in the brain. CHD8 is an essential gene during mouse development and CHD8 haploinsufficiency has been shown to impact early neurodevelopment. However, work in mouse models has also shown that Chd8 haploinsufficiency leads to synaptic pathology. Published mouse models of Chd8 have focused on constitutive germline mutation, making it impossible to disentangle developmental from postnatal requirements for Chd8 or to define cell-type specific effects of Chd8 mutation in neurons. My research will address this key gap in knowledge, defining region-specific perturbations to transcription in the mouse brain caused by Chd8 haploinsufficiency and testing whether conditional Chd8 mutation in postnatal neurons is sufficient to recapitulate NDD-relevant transcriptional and behavioral pathology reported in mice with constitutive germline Chd8 mutations. This work will definitively address a central question in the field relevant to understanding how CRF mutations cause behavioral pathology: whether cognitive and behavioral pathology is caused by developmental perturbation or, alternatively, if pathology is caused by disruption to ongoing requirement for Chd8 expression in mature neurons. The results from this study will significantly improve knowledge of the role of CHD8, and more generally CRFs, in the brain and as a causal factor in NDDs. Towards eventual improvements in diagnosis and treatment of NDDs, characterizing how CHD8-dependent chromatin remodeling activity contributes to synaptic pathology in neurons could reveal novel postnatal pharmacological interventions for both patients with CHD8 mutations and for patients with mutations to CRFs in general.

Public Health Relevance

Mutations to chromatin remodeling factors, which control DNA accessibility required for transcription and differentiation, have recently been implicated in autism spectrum disorder. Chd8 is a chromatin remodeling factor with one of the highest de novo mutation rates in patients, but it is unclear whether phenotypes from these mutations are selectively caused by early developmental disruptions or whether pathology also arises later in life. The research in this proposal aims to test whether postnatal-specific Chd8 mutations are sufficient to cause synaptic and behavioral phenotypes typically observed with Chd8 haploinsufficiency to further our understanding of the biological underpinnings of ASD and general chromatin remodeler function.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Driscoll, Jamie
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University of California Davis
Schools of Medicine
United States
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