In vivo targeted DamID identifies CHD8 genomic targets in fetal mouse brain

A Ayanna Wade,Jelle Van Den Ameele,Seth W Cheetham,Rebecca Yakob,Andrea H Brand,Alex S Nord

doi:10.1016/j.isci.2021.103234

A Ayanna Wade, Jelle Van Den Ameele + Show 4 more

Open Access

https://doi.org/10.1016/j.isci.2021.103234

Copy DOI

Abstract

SummaryGenetic studies of autism have revealed causal roles for chromatin remodeling gene mutations. Chromodomain helicase DNA binding protein 8 (CHD8) encodes a chromatin remodeler with significant de novo mutation rates in sporadic autism. However, relationships between CHD8 genomic function and autism-relevant biology remain poorly elucidated. Published studies utilizing ChIP-seq to map CHD8 protein-DNA interactions have high variability, consistent with technical challenges and limitations associated with this method. Thus, complementary approaches are needed to establish CHD8 genomic targets and regulatory functions in developing brain. We used in utero CHD8 Targeted DamID followed by sequencing (TaDa-seq) to characterize CHD8 binding in embryonic mouse cortex. CHD8 TaDa-seq reproduced interaction patterns observed from ChIP-seq and further highlighted CHD8 distal interactions associated with neuronal loci. This study establishes TaDa-seq as a useful alternative for mapping protein-DNA interactions in vivo and provides insights into the regulatory targets of CHD8 and autism-relevant pathophysiology associated with CHD8 mutations.

Highlights

Neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD) and intellectual disability (ID) are complex disorders caused by genetic and environmental factors that disrupt brain development
We used in utero Chromodomain helicase DNA binding protein 8 (CHD8) Targeted DamID followed by sequencing (TaDa-seq) to characterize CHD8 binding in embryonic mouse cortex
CHD8 TaDa-seq reproduced interaction patterns observed from ChIP-seq and further highlighted CHD8 distal interactions associated with neuronal loci

Summary

Introduction

Neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD) and intellectual disability (ID) are complex disorders caused by genetic and environmental factors that disrupt brain development. Genetic studies have identified an overlapping set of genes that, when mutated, greatly increase risk for both ASD and ID (O’Roak et al, 2012a, 2012b; Parikshak et al, 2013; De Rubeis et al, 2014; Iossifov et al, 2014; Sanders et al, 2015; Vissers et al, 2016; Satterstrom et al, 2020) Of these shared risk gene sets, a striking and surprising finding has been the strong enrichment of case mutations in genes that encode proteins involved in chromatin remodeling (O’Roak et al, 2012a; De Rubeis et al, 2014). The function of CHD8 and other NDD-associated chromatin remodeling proteins in developing brain remains poorly characterized, representing a major barrier to understanding the neurodevelopmental mechanisms of NDDs

Results

Discussion

Conclusion