Directionality of transcriptional regulatory elements.

Divergent transcription is a critical marker of active transcriptional regulatory elements (TREs), including enhancers and promoters, in mammals. However, distal elements with unidirectional transcriptional patterns are often overlooked, leaving their identity and function poorly understood. Here, we perform a systematic comparison between divergent and unidirectional elements, revealing their distinct architectural and functional features. Our analysis also shows that unidirectional elements have younger sequence ages and are under weaker evolutionary constraints than divergent elements, suggesting that they may represent a unique category of genomic regulatory function with more recent origins. Furthermore, we investigate factors involved in transcriptional directionality at TREs, with CTCF and ZNF143 showing dual, position-dependent roles in transcriptional modulation. Overall, the elucidation of directionality enhances our understanding of the diverse architectural models, functional features, evolutionary dynamics, and regulatory logic of TREs.