# Epigenomic dysfunction at 16q24.1 vascular defects and perinatal consequences

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $488,717

## Abstract

Epigenomic dysfunction at 16q24.1 – vascular defects and perinatal consequences.
ABSTRACT
Heterozygous genomic deletions and point mutations in the FOXF1 cause Alveolar Capillary Dysplasia with
Misalignment of Pulmonary Veins (ACDMPV), a neonatally lethal developmental lung disease. The vast
majority of ACDMPV patients have additional defects involving heart, gastrointestinal, or genitourinary
systems. The mesenchymal FOXF1 transcription factor expressed in the endothelial and smooth muscle cells
plays an important role in epithelium-mesenchyme signaling, as a downstream target of Sonic hedgehog
pathway. We accumulated the largest collection of ACDMPV samples in the world (N~145 families). Recently,
we found that genomic deletions mapping in a protein-coding gene desert ~270 kb upstream to FOXF1 and
leaving it intact manifest with the full ACDMPV phenotype. These deletions enabled us to define an ~60 kb
tissue-specific enhancer region harboring long non-coding RNAs (lncRNAs), LINC01081 and LINC01082, that
are expressed in fetal lungs. Another lncRNA, FENDRR that maps 1.7 kb upstream of FOXF1 in the opposite
orientation and likely utilizes the same bi-directional promoter as FOXF1, interacts with chromatin-modifying
complex (PRC) 2 to regulate gene expression. Interestingly, homozygous loss of Fendrr, leaving Foxf1 intact,
leads to lethal defects of lungs and heart in mouse neonates. Importantly, we found that the FOXF1 locus is
imprinted, likely using these lncRNAs; 31/32 of the characterized genomic deletions arose de novo on maternal
chromosome 16q24.1. Trisomy 16 in humans, resulting from maternal meiosis I nondisjunction, is the most
common prenatal trisomy (>1% of all pregnancies) and lethal unless rescued early embryonically. In one-third
of such cases, children with maternal UPD(16) manifest IUGR (attributed to trisomic placenta) and multiple
congenital malformations, including heart defects, pulmonary hypoplasia, tracheosophageal fistula, gut
malrotation, absent gall bladder, renal agenesis, hydronephrosis, imperforate anus, and single umbilical artery.
Interestingly, all the above clinical features, except IUGR, are observed in the vast majority of children with
ACDMPV. In contrast, relatively normal phenotype was reported in few patients with paternal UPD(16), and
imprinted gene(s) on chromosome 16 were suggested as causative for maternal UPD(16) phenotype. We
hypothesize that FOXF1 enhancer and lncRNAs play an important role in genomic imprinting at 16q24.1, which
may be responsible for the key features of maternal UPD(16). In aim 1, we will study the role of genomic
imprinting of the FOXF1 locus in ACDMPV and UPD(16). In aim 2, we will analyze the function of the FOXF1
enhancer, including the overlapping lncRNAs. In aim 3, we will investigate the function of FENDRR in
development and disease of heart, lung, and placenta. The proposed studies would provide a better
understanding of the function of distant tissue-specific enhancers in g...

## Key facts

- **NIH application ID:** 9922356
- **Project number:** 5R01HL137203-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** PAWEL STANKIEWICZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $488,717
- **Award type:** 5
- **Project period:** 2017-05-22 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922356

## Citation

> US National Institutes of Health, RePORTER application 9922356, Epigenomic dysfunction at 16q24.1 vascular defects and perinatal consequences (5R01HL137203-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9922356. Licensed CC0.

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