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Peer-reviewedCC BY 4.0Proceedings of the National Academy of Sciences of the United States of America

Regulation of morphogen signaling pathways by recurrent hypermotif circuits

  • Miri Adler1,2,3
  • Ruslan Medzhitov3,4,5
5 affiliations
  1. 1Department of Genetics, Silberman Institute of Life Science, Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
  2. 2Department of Immunology and Cancer Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
  3. 3Tananbaum Center for Theoretical and Analytical Human Biology, Yale University School of Medicine, New Haven, CT 06510
  4. 4Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
  5. 5HHMI, Yale University School of Medicine, New Haven, CT 06510
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{adler2026regulation,
  title = {{Regulation of morphogen signaling pathways by recurrent hypermotif circuits}},
  author = {Miri Adler and Ruslan Medzhitov},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2538060123},
  url = {https://doi.org/10.1073/pnas.2538060123},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Regulation of morphogen signaling pathways by recurrent hypermotif circuits
AU  - Miri Adler
AU  - Ruslan Medzhitov
PY  - 2026
DA  - 2026/10/05
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2538060123
UR  - https://doi.org/10.1073/pnas.2538060123
AB  - 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.
SN  - 0027-8424
SN  - 1091-6490
ER  -