Facilitators may represent a new class of regulatory elements.

Gene expression is controlled by three main cis-regulatory elements: enhancers, promoters, and insulators. When active and bound by transcription factors, co-factors, and architectural proteins, these elements together shape the genome's structure and function. Although each class has distinct features, the functions of these classes often overlap. Chromatin analyses suggest that the mammalian genome contains over a million cis-regulatory elements. Many are classified as enhancers based on chromatin signatures, and yet they may not act as classical enhancers in traditional assays. However, these enhancer-like elements can augment enhancer activity in their native chromosomal context. We refer to these as 'facilitators.' The mechanisms by which facilitators regulate gene expression remain unclear, though two possibilities are proposed. First, facilitators may supply essential factors or raise their concentration to form transcriptional hubs that enhance gene expression. Second, they might help organise chromatin architecture, bringing enhancers and promoters into proximity to increase their interaction. We discuss current evidence suggesting that this subset of uncharacterised cis-acting sequences may constitute a distinct class of regulatory elements that facilitate classical enhancer activity.