RT Journal
A1 Szafranski, Przemyslaw
A1 Dharmadhikari, Avinash V.
A1 Brosens, Erwin
A1 Gurha, Priyatansh
A1 Kołodziejska, Katarzyna E.
A1 Zhishuo, Ou
A1 Dittwald, Piotr
A1 Majewski, Tadeusz
A1 Mohan, K. Naga
A1 Chen, Bo
A1 Person, Richard E.
A1 Tibboel, Dick
A1 de Klein, Annelies
A1 Pinner, Jason
A1 Chopra, Maya
A1 Malcolm, Girvan
A1 Peters, Gregory
A1 Arbuckle, Susan
A1 Guiang, Sixto F.
A1 Hustead, Virginia A.
A1 Jessurun, Jose
A1 Hirsch, Russel
A1 Witte, David P.
A1 Maystadt, Isabelle
A1 Sebire, Neil
A1 Fisher, Richard
A1 Langston, Claire
A1 Sen, Partha
A1 Stankiewicz, Paweł
T1 Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder
JF Genome Research 
JO Genome Research 
YR 2013 
FD January 01 
VO 23 
IS 1 
SP 23 
OP 33 
DO 10.1101/gr.141887.112 
UL http://genome.cshlp.org/content/23/1/23.abstract 
AB 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.