Details

Autor(en) / Beteiligte

• Szafranski, Przemyslaw
• Dharmadhikari, Avinash V
• Brosens, Erwin
• Gurha, Priyatansh
• Kolodziejska, 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, 3rd, Sixto F
• Hustead, Virginia A
• Jessurun, Jose
• Hirsch, Russel
• Witte, David P
• Maystadt, Isabelle
• Sebire, Neil
• Fisher, Richard
• Langston, Claire
• Sen, Partha
• Stankiewicz, Paweł

Titel

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

Ist Teil von

• Genome research, 2013-01, Vol.23 (1), p.23

Ort / Verlag

United States

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.