Author:
Szafranski Przemyslaw,Dharmadhikari Avinash V.,Brosens Erwin,Gurha Priyatansh,Kołodziejska Katarzyna E.,Zhishuo Ou,Dittwald Piotr,Majewski Tadeusz,Mohan K. Naga,Chen Bo,Person Richard E.,Tibboel Dick,de Klein Annelies,Pinner Jason,Chopra Maya,Malcolm Girvan,Peters Gregory,Arbuckle Susan,Guiang Sixto F.,Hustead Virginia A.,Jessurun Jose,Hirsch Russel,Witte David P.,Maystadt Isabelle,Sebire Neil,Fisher Richard,Langston Claire,Sen Partha,Stankiewicz Paweł
Abstract
An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) 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 lncRNA 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 lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA 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 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.
Publisher
Cold Spring Harbor Laboratory
Subject
Genetics (clinical),Genetics
Cited by
122 articles.
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