Mechanisms defining enhancer–promoter recognition.

(A) TAD boundaries pose spatial constraint, allowing for specific enhancer–promoter interactions. (B) Enhancer activity could be obscured by its localization to repressive chromatin compartments. (C) Enhancer–promoter targeting can depend upon the binding compatibility of the transcription factors bound to two interacting loci, termed biochemical compatibility. (D) Insulator elements bound by insulator factors facilitate specific enhancer interaction and eliminate nonspecific enhancer–promoter crosstalk. (E) Noncoding RNA or enhancer RNA (eRNA) transcribed from the enhancer can define its interaction with the target promoter.