Mechanisms of enhancer function in neuronal systems in health and disease

Enhancers are genomic elements that regulate gene expression through a variety of mechanisms. In neuronal systems, enhancer-promoter interactions regulate cell- and tissue-specific transcriptional programs, during neuronal specification and upon terminal differentiation, and play major roles in the tight regulation of activity-dependent mechanisms, such as in memory formation. Enhancers are also hotspots for non-coding genetic variants associated with neurological disorders, such as schizophrenia and Parkinson's disease (PD). Understanding how enhancer grammar informs gene expression programs in neuronal systems in development and disease remains a major challenge, and is a growing avenue to discover the molecular mechanisms directly altered by non-coding genetic variants. In this review, we discuss the diverse mechanisms by which enhancers integrate internal and external stimuli to regulate the gene expression programs that guide neuronal specification and sustain neuronal-specific and activity-dependent processes.