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Identification of endothelial and mesenchymal FOXF1 enhancers involved in alveolar capillary dysplasia

Author

Listed:
  • Guolun Wang

    (Cincinnati Children’s Research Foundation
    University of Cincinnati College of Medicine)

  • Bingqiang Wen

    (College of Medicine - Phoenix)

  • Minzhe Guo

    (Cincinnati Children’s Research Foundation
    University of Cincinnati College of Medicine)

  • Enhong Li

    (College of Medicine - Phoenix)

  • Yufang Zhang

    (Cincinnati Children’s Research Foundation)

  • Jeffrey A. Whitsett

    (Cincinnati Children’s Research Foundation
    University of Cincinnati College of Medicine)

  • Tanya V. Kalin

    (College of Medicine - Phoenix)

  • Vladimir V. Kalinichenko

    (College of Medicine - Phoenix
    Phoenix Children’s Hospital)

Abstract

Mutations in the FOXF1 gene, a key transcriptional regulator of pulmonary vascular development, cause Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins, a lethal lung disease affecting newborns and infants. Identification of new FOXF1 upstream regulatory elements is critical to explain why frequent non-coding FOXF1 deletions are linked to the disease. Herein, we use multiome single-nuclei RNA and ATAC sequencing of mouse and human patient lungs to identify four conserved endothelial and mesenchymal FOXF1 enhancers. We demonstrate that endothelial FOXF1 enhancers are autoactivated, whereas mesenchymal FOXF1 enhancers are regulated by EBF1 and GLI1. The cell-specificity of FOXF1 enhancers is validated by disrupting these enhancers in mouse embryonic stem cells using CRISPR/Cpf1 genome editing followed by lineage-tracing of mutant embryonic stem cells in mouse embryos using blastocyst complementation. This study resolves an important clinical question why frequent non-coding FOXF1 deletions that interfere with endothelial and mesenchymal enhancers can lead to the disease.

Suggested Citation

  • Guolun Wang & Bingqiang Wen & Minzhe Guo & Enhong Li & Yufang Zhang & Jeffrey A. Whitsett & Tanya V. Kalin & Vladimir V. Kalinichenko, 2024. "Identification of endothelial and mesenchymal FOXF1 enhancers involved in alveolar capillary dysplasia," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49477-6
    DOI: 10.1038/s41467-024-49477-6
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    3. Astrid Gillich & Fan Zhang & Colleen G. Farmer & Kyle J. Travaglini & Serena Y. Tan & Mingxia Gu & Bin Zhou & Jeffrey A. Feinstein & Mark A. Krasnow & Ross J. Metzger, 2020. "Capillary cell-type specialization in the alveolus," Nature, Nature, vol. 586(7831), pages 785-789, October.
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