Title:Genomic and Epigenetic Complexity of the FOXF1 Locus in 16q24.1: Implications for Development and Disease
Volume: 16
Issue: 2
Author(s): Avinash V. Dharmadhikari, Przemyslaw Szafranski, Vladimir V. Kalinichenko and Pawel Stankiewicz
Affiliation:
Keywords:
ACDMPV, Gene regulation, Genomic-imprinting, Long non-coding RNA, Lung development, Pulmonary vasculature.
Abstract: The FOXF1 (Forkhead box F1) gene, located on chromosome 16q24.1 encodes a member of the
FOX family of transcription factors characterized by a distinct forkhead DNA binding domain. FOXF1
plays an important role in epithelium-mesenchyme signaling, as a downstream target of Sonic hedgehog
pathway. Heterozygous point mutations and genomic deletions involving FOXF1 have been reported in
newborns with a lethal lung developmental disorder, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins
(ACDMPV). In addition, genomic deletions upstream to FOXF1 identified in ACDMPV patients have revealed
that FOXF1 expression is tightly regulated by distal tissue-specific enhancers. Interestingly, FOXF1 has been found to be
incompletely paternally imprinted in human lungs; characterized genomic deletions arose de novo exclusively on maternal
chromosome 16, with most of them being Alu-Alu mediated. Regulation of FOXF1 expression likely utilizes a combination
of chromosomal looping, differential methylation of an upstream CpG island overlapping GLI transcription factor
binding sites, and the function of lung-specific long non-coding RNAs (lncRNAs). Foxf1 knock-out mouse models demonstrated
its critical role in mesoderm differentiation and in the development of pulmonary vasculature. Additionally, epigenetic
inactivation of FOXF1 has been reported in breast and colorectal cancers, whereas overexpression of FOXF1 has
been associated with a number of other human cancers, e.g. medulloblastoma and rhabdomyosarcoma. Constitutional duplications
of FOXF1 have recently been reported in congenital intestinal malformations. Thus, understanding the genomic
and epigenetic complexity at the FOXF1 locus will improve diagnosis, prognosis, and treatment of ACDMPV and other
human disorders associated with FOXF1 alterations.
