Recurrent hypermotif regulatory circuits in developmental programs

Abstract

During development, cells self-organize into complex spatial and temporal patterns driven by regulatory circuits of transcription factors and morphogen signaling. However, the principles that govern these regulatory interactions remain poorly understood. Here, we introduce a framework to dissect the building-block circuits of developmental gene regulatory networks and explore their integration into higher-order hypermotif circuits. Using single-cell RNA-sequencing data spanning human intestinal development, we identify five recurrent network motifs, including feedforward and feedback loops, and investigate their roles in the regulation of gene expression. Our analysis reveals distinct categories of developmental genes based on their roles within network motifs, highlighting major transitions in regulatory architecture across developmental stages. Furthermore, we model the emergent dynamical properties of hypermotif circuits, including their potential roles in regulating morphogen signaling. This study uncovers a common theme in regulatory circuits of developmental programs, emphasizing how the combinatorial wiring of regulatory motifs enables robust and diverse tissue formation.

The authors' abstract, as published at the source. Proceedings of the National Academy of Sciences, 2026 · DOI ↗