Genome Editing Technologies for Investigation of Activity-Dependent Transcription

Experience-driven gene transcription is a core mechanism underlying neurodevelopment, neuronal plasticity, learning, and both adaptive and maladaptive forms of behavior. Functional links between activity-regulated genes and cellular or behavioral phenotypes were initially discovered using classic gene knockout, knockdown, or overexpression approaches. However, these tools often lacked cellular and genetic precision, and were not capable of probing specific gene regulatory states or mimicking the dynamic nature of activity-dependent gene expression. In the past decade, rapid advances in gene editing technologies such as CRISPR/Cas9 have enabled the development of custom methods for mechanistic perturbation of the genome and epigenome. These precision editing tools have shaped our understanding of the molecular roles for activity-driven gene programs, and generated new insights into the mechanisms by which experience modifies gene expression dynamics in neurons. This chapter will highlight recent advances in the application of CRISPR systems for gene activation, repression, and chromatin modifications, discuss recent advances in multiplexed and inducible gene regulation, and identify future research directions in the use of gene editing tools for understanding activity-dependent transcription.