Identification of Endothelial and Mesenchymal FOXF1 Enhancers Involved in Alveolar Capillary Dysplasia

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jun 19

PMID 38898031

Authors

Guolun Wang

Bingqiang Wen

Minzhe Guo

Enhong Li

Yufang Zhang

Jeffrey A Whitsett

Tanya V Kalin

Vladimir V Kalinichenko

Affiliations

Soon will be listed here.

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.

Citing Articles

The molecular consequences of FOXF1 missense mutations associated with alveolar capillary dysplasia with misalignment of pulmonary veins.

Edel G, van Kempen M, Munck A, Huisman C, Naalden C, Brouwer R J Biomed Sci. 2024; 31(1):100.

PMID: 39497128 PMC: 11536904. DOI: 10.1186/s12929-024-01088-5.

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