Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung...

Area of Science:

• Genomics
• Developmental Biology
• Molecular Genetics

Background:

• The human genome contains a vast amount of noncoding DNA, with long noncoding RNAs (lncRNAs) being a significant transcribed fraction whose functions are largely unknown.
• Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a severe, often lethal, congenital lung disorder.
• Parent-of-origin effects suggest a role for genomic imprinting or differential gene regulation based on parental inheritance.

Observation:

• Overlapping deletions, specifically on the maternally inherited chromosome, were identified in nine patients with ACD/MPV.
• These deletions, located 250 kb upstream of the FOXF1 gene, affect a differentially methylated region and include lung-specific lncRNA genes.
• The deleted region contains a CpG island that binds GLI2 in a methylation-dependent manner and interacts with the FOXF1 promoter.

Findings:

• The deletions define a distant cis-regulatory element critical for lung development.
• Lung-specific lncRNAs within this region appear to play a role in the long-range regulation of FOXF1 expression, potentially mediated by transcription factors like GLI2.
• The findings link specific lncRNA genes to a severe developmental disorder.

Implications:

• This study highlights the crucial role of lncRNAs in regulating gene expression during human development.
• Dysregulation of lncRNA-mediated chromatin interactions could be a mechanism underlying various developmental disorders.
• Understanding these regulatory mechanisms may open new avenues for diagnosing and potentially treating congenital lung diseases.