Abstract
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 performed 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, indicating that they may represent a unique category of genomic regulatory function with more recent origins. Notably, we observed that some transcription factors, including CTCF, AP1, SP, and NFY, exhibit dual roles in modulating the directionality of TREs, either activating or repressing nascent transcription in a position-dependent manner. Overall, the elucidation of directionality enhances our understanding of the diverse architectural models, functional features, evolutionary dynamics, and regulatory logic of TREs.
Competing Interest Statement
S.R.S. is an equity holder and member of the scientific advisory board of NeuScience, Inc., and a consultant at Third Bridge Group Limited, which are not related to this work. A.K. is on the scientific advisory board of SerImmune, AIN- ovo, TensorBio and OpenTargets. A.K was a scientific co- founder of RavelBio, a paid consultant with Illumina, was on the SAB of PatchBio and owns shares in DeepGenomics, Immunai, Freenome and Illumina. K.C. is a paid consultant with ImmunoVec and owns shares in Inceptive Nucleics. The remaining authors declare no competing interests.