Small noncoding differentially methylated copy-number variants, including IncRNA genes, cause a lethal lung developmental disorder

• Published in: Genome research 2013-01, Vol.23 (1), p.23-33
• Main Authors: Szafranski, P, Dharmadhikari, A V, Brosens, E, Gurha, P, Kolodziejska, KE, Zhishuo, O, Dittwald, P, Majewski, T, Mohan, K N, Chen, B, Person, R E, Tibboel, D, de Klein, A, Stankiewicz, P
• Format: Article
• Language: English
• ISSN: 1088-9051

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (IncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including IncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific IncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides IncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 IncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of IncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.