RT Journal Article
SR Electronic
T1 Disruption of normal patterns of FOXF1 expression in a lethal disorder of lung development
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2019-106095
DO 10.1136/jmedgenet-2019-106095
A1 Laurie A Steiner
A1 Michael Getman
A1 Gillian M Schiralli Lester
A1 M Anwar Iqbal
A1 Philip Katzman
A1 Przemyslaw Szafranski
A1 Pawel Stankiewicz
A1 Soumyaroop Bhattacharya
A1 Thomas Mariani
A1 Gloria Pryhuber
A1 Xin Lin
A1 Jennifer L Young
A1 David A Dean
A1 Kristin Scheible
YR 2019
UL http://jmg.bmj.com/content/early/2019/10/29/jmedgenet-2019-106095.abstract
AB 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.