Model. (1) An active enhancer physically interacts with a boundary and activates boundary RNA transcription. (2) The boundary RNA in return stabilizes the CTCF at these boundaries, thereby (3) strengthening insulation of these TADs. (4) This favors intra-TAD enhancer–promoter interactions to facilitate robust gene transcription. The loss of boundary RNA/enhancer deletion reduces the boundary RNA levels, which triggers the loss of CTCF and insulation of TADs. Enhancer–promoter interactions weaken in these scenarios, which causes concomitant loss of gene transcription.