Regulation of morphogen signaling pathways by recurrent hypermotif circuits.

Morphogen signaling pathways orchestrate cell fate and tissue patterning during embryo development through intricate intercellular communication. While much is known about the molecular components of these pathways, the underlying regulatory logic shaping their integration remains unclear. Here, we develop a computational framework to uncover higher-order network structures, hypermotifs, that link gene regulatory circuits within and between cells via morphogen signaling. Applying this framework to single-cell RNA sequencing data from human intestinal development, we identify recurrent hypermotif topologies that mediate communication between epithelial and fibroblast populations. These cell-cell hypermotif circuits involve feedback and feedforward loops embedded within signaling pathways. Dynamical modeling reveals that such circuits can generate emergent behaviors, including oscillatory and antagonistic responses. Our results highlight hypermotifs as key design principles in developmental regulatory networks, providing a systems-level understanding of morphogen signal integration across cell types.