Actors with Multiple Roles: Pleiotropic Enhancers and the Paradigm of Enhancer Modularity

The current paradigm in the field of gene regulation postulates that regulatory information for generating gene expression is organized into modules (enhancers), each containing the information for driving gene expression in a single spatiotemporal context. This modular organization is thought to facilitate the evolution of gene expression by minimizing pleiotropic effects. Here we review recent studies that provide evidence of quite the opposite: (i) enhancers can function in multiple developmental contexts, implying that enhancers can be pleiotropic, (ii) transcription factor binding sites within pleiotropic enhancers are reused in different contexts, and (iii) pleiotropy impacts the structure and evolution of enhancers. Altogether, this evidence suggests that enhancer pleiotropy is pervasive in animal genomes, challenging the commonly held view of modularity. Recent genome-wide and locus-specific functional studies uncovered that enhancer pleiotropy is pervasive in gene regulatory regions of animal genomes.Transcription factor binding sites within pleiotropic enhancers can be reused in different contexts, implying that binding sites can be pleiotropic.Pleiotropic enhancers are more constrained and have distinctive structural features when compared with tissue-specific enhancers.The extent of pleiotropy in enhancer function weakens the commonly held view of enhancers as being strictly tissue-specific regulatory elements.Comprehensive screens of enhancer activity and transcription factor binding site function over multiple contexts and across organisms will shed light on the mechanisms underlying enhancer pleiotropy.