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

Guolun Wang (), Bingqiang Wen, Minzhe Guo, Enhong Li, Yufang Zhang, Jeffrey A. Whitsett, Tanya V. Kalin and Vladimir V. Kalinichenko ()
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Guolun Wang: Cincinnati Children’s Research Foundation
Bingqiang Wen: College of Medicine - Phoenix
Minzhe Guo: Cincinnati Children’s Research Foundation
Enhong Li: College of Medicine - Phoenix
Yufang Zhang: Cincinnati Children’s Research Foundation
Jeffrey A. Whitsett: Cincinnati Children’s Research Foundation
Tanya V. Kalin: College of Medicine - Phoenix
Vladimir V. Kalinichenko: College of Medicine - Phoenix

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49477-6

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