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

Przemyslaw Szafranski, Avinash V. Dharmadhikari, Erwin Brosens, Priyatansh Gurha, Katarzyna E. Kołodziejska, Ou Zhishuo, Piotr Dittwald, Tadeusz Majewski, K. Naga Mohan, Bo Chen, Richard E. Person, Dick Tibboel, Annelies De Klein, Jason Pinner, Maya Chopra, Girvan Malcolm, Gregory Peters, Susan Arbuckle, Sixto F. Guiang, Virginia A. HusteadJose Jessurun, Russel Hirsch, David P. Witte, Isabelle Maystadt, Neil Sebire, Richard Fisher, Claire Langston, Partha Sen, Paweł Stankiewicz

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

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 IncRNAgenes. These deletions define a distant cis-regulatory region that harbors, besides lncRNAgenes, also a differentially methylated CpGisland, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. Wesuggest 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.

Original languageEnglish (US)
Pages (from-to)22-33
Number of pages12
JournalGenome research
Volume23
Issue number1
DOIs
StatePublished - Jan 2013

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