In vivo locus-specific editing of the neuroepigenome

• Published in: Nature reviews. Neuroscience 2020-09, Vol.21 (9), p.471-484
• Main Authors: Yim, Yun Young, Teague, Collin D., Nestler, Eric J.
• Format: Article
• Language: English
• Subjects: 631/1647/1513; 631/378/2584/1695; Animal behavior; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain Diseases - genetics; Chromatin; Chromatin - genetics; CRISPR; Editing; Epigenesis, Genetic - genetics; Epigenetic inheritance; Epigenetics; Epigenomics - methods; Gene Editing - methods; Gene loci; Genes; Humans; Medical research; Medicine, Experimental; Nervous system diseases; Neurobiology; Neurological diseases; Neurosciences; Regulatory proteins; Review Article; Transcription; Zinc finger proteins
• ISSN: 1471-003X; 1471-0048; 1469-3178
• DOI: 10.1038/s41583-020-0334-y

Studies over the past several decades have identified numerous epigenetic mechanisms associated with pathological states in psychiatric and neurological disease. Until recently, studies investigating chromatin-regulatory proteins, using overexpression or knockdown approaches, did not establish causal roles for epigenetic modifications at specific genes because these techniques typically affect hundreds or thousands of genomic loci. In this Review, we describe recent efforts in using locus-specific neuroepigenome editing in vivo to, for the first time, define causal relationships between a single chromatin modification at a specific gene in a defined cell population and downstream measures at the molecular, cellular, circuit and behavioural levels. We briefly introduce three epigenome-editing platforms: zinc-finger proteins, transcriptional activator-like effectors and clustered regularly interspaced short palindromic repeats (CRISPR). We then explore the development of in vivo neuroepigenome-editing tools and their applications to resolve epigenetic contributions to the pathophysiology of brain diseases. We also discuss technical considerations for in vivo neuroepigenome-editing experiments and ongoing innovations in the field, including new tools to investigate chromatin marks, manipulate chromatin topology and induce epigenetic modifications at multiple genes in the same cell. Lastly, we explore the potential clinical applications of in vivo neuroepigenome editing for treating brain pathology. The causal role of chromatin modifications has been difficult to study in the brains of behaving animals. Yim, Teague and Nestler review locus-specific neuroepigenome-editing tools to define causal relationships between chromatin modifications and their molecular, cellular, circuit and behavioural consequences.