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

Recurrent hypermotif regulatory circuits in developmental programs

  • Miri Adler1,2,3
  • Ruslan Medzhitov3,4,5
5 affiliations
  1. 1Department of Genetics, Silberman Institute of Life Science, 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

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.

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Cite

BibTeXRIS
BibTeX
@article{adler2026recurrent,
  title = {{Recurrent hypermotif regulatory circuits in developmental programs}},
  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.2538056123},
  url = {https://doi.org/10.1073/pnas.2538056123},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Recurrent hypermotif regulatory circuits in developmental programs
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.2538056123
UR  - https://doi.org/10.1073/pnas.2538056123
AB  - 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.
SN  - 0027-8424
SN  - 1091-6490
ER  -