Background Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a lethal disorder of lung development. ACDMPV is associated with haploinsufficiency of the transcription factor FOXF1, which plays an important role in the development of the lung and intestine. CNVs upstream of the FOXF1 gene have also been associated with an ACDMPV phenotype, but mechanism(s) by which these deletions disrupt lung development are not well understood. The objective of our study is to gain insights into the mechanisms by which CNVs contribute to an ACDMPV phenotype.
Methods We analysed primary lung tissue from an infant with classic clinical and histological findings of ACDMPV and harboured a 340 kb deletion on chromosome 16q24.1 located 250 kb upstream of FOXF1.
Results In RNA generated from paraffin-fixed lung sections, our patient had lower expression of FOXF1 than age-matched controls. He also had an abnormal pattern of FOXF1 protein expression, with a dramatic loss of FOXF1 expression in the lung. To gain insights into the mechanisms underlying these changes, we assessed the epigenetic landscape using chromatin immunoprecipitation, which demonstrated loss of histone H3 lysine 27 acetylation (H3K27Ac), an epigenetic mark of active enhancers, in the region of the deletion.
Conclusions Together, these data suggest that the deletion disrupts an enhancer responsible for directing FOXF1 expression in the developing lung and provide novel insights into the mechanisms underlying a fatal developmental lung disorder.
- other respiratory medicine
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Contributors LAS, DAD, JLY and KS designed experiments, analysed data and wrote the manuscript. TM, GP and SB analysed data, assembled figures and reviewed the manuscript. XL, MG and GMSL performed experiments and analysed data. PrS, PaS, PK and MAI performed experiments, analysed data and reviewed the manuscript.
Funding National Heart, Lung, and Blood Institute Molecular Atlas of Lung Development Program Human Tissue Core (LungMAP-HTC) Grant U01-HL-122700 (GP, TM and SB).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All studies were approved by the University of Rochester Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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