Cooperativity between regulatory elements acts as a modulator of enhancer function

Transcription is classically known to be regulated by two key elements, promoters and enhancers. While these remain central to gene regulation, it is now clear that additional regulatory sequences fine-tune enhancer function and transcriptional output. In this review, we focus on two such recently described sequences, promoter-proximal elements and enhancer-like modulators, highlighting representative examples of their function and their proposed mechanisms of action. We further discuss the implications of these discoveries on the current definitions of promoters and enhancers, and highlight an emerging theme that such elements do not fall into discrete classes but instead function along a regulatory continuum. Recognizing this continuum and appreciating transcriptional control as an interconnected network of elements will be essential for understanding gene regulation in complex genomes.