Abstract

Cis‐regulatory elements govern gene expression programs to determine cell identity during development. Recently, the possibility that multiple enhancers are orchestrated in clusters of enhancers has been suggested. How these elements are arranged in the 3D space to control the activation of a specific promoter remains unclear. Our recent work revealed that the TGFβ pathway drives the assembly of enhancer clusters and precise gene activation during neurogenesis. We discovered that the TGFβ pathway coactivator JMJD3 was essential in maintaining these structures in the 3D space. To do that, JMJD3 required an intrinsically disordered region involved in forming phase‐separated biomolecular condensates found in the enhancer clusters. Our data support the existence of a relationship between 3D‐conformation of the chromatin, biomolecular condensates, and TGFβ‐driven response during mammalian neurogenesis. In this review, we discuss how signaling (TGFβ), epigenetics (JMJD3), and biochemical properties (biomolecular condensates nucleation) are coordinated to modulate the genome structure to guarantee proper neural development. Moreover, we comment on the potential underlying mechanisms and implications of the enhancer‐mediated regulation. Finally, we point out the knowledge gaps that still need to be addressed.