Editing the Epigenome to Tackle Brain Disorders

Genetic studies of epigenetic modifiers such as DNA methyltransferases and histone acetyltransferases have revealed a critical role for epigenetic regulation during brain development and function. Alteration of epigenetic modifications have been documented in a variety of brain disorders, including neurodevelopmental, psychiatric, and neurodegenerative diseases. Development of epigenome editing tools enables a functional dissection of the link between altered epigenetic changes and disease outcomes. Here, we review the development of epigenome editing tools, summarize proof of concept applications focusing on brain disease-associated genes, and discuss the promising application and challenges of epigenome editing to tackle brain disorders. Current understanding of the epigenome is based on the systematic profiling of the epigenetic landscape in multiple tissues during development and pathogenesis of diseases.Development and application of epigenome editing tools has been accelerated by the discovery of the CRISPR/Cas9 system, allowing for locus-specific targeting of epigenetic effectors to any given genomic locus, through easy design and assembly of single guide RNA.Epigenome editing tools enable us to distinguish correlation and causality of epigenetic events associated with brain diseases.Off-target effects and stability of epigenome editing are two major considerations for any therapeutic application.Expansion of editing tools by introduction of other orthologs in the CRISPR/Cas systems will allow for simultaneous modifications of multiple genomic loci at different layers of epigenetic marks, enabling us to tackle polygenic disorders.