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23034409
Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.

Genome Res, 2013/1;23(1):23-33.

Szafranski P[1], Dharmadhikari AV, Brosens E, Gurha P, Kolodziejska KE, Zhishuo O, Dittwald P, Majewski T, Mohan KN, Chen B, Person RE, Tibboel D, de Klein A, Pinner J, Chopra M, Malcolm G, Peters G, Arbuckle S, Guiang SF 3rd, Hustead VA, Jessurun J, Hirsch R, Witte DP, Maystadt I, Sebire N, Fisher R, Langston C, Sen P, Stankiewicz P

Affiliations

PMID: 23034409DOI: 10.1101/gr.141887.112

Impact factor: 9.438

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.
MeSH terms
Chromatin; Chromosomes, Human, Pair 16; CpG Islands; DNA Copy Number Variations; DNA Methylation; Enhancer Elements, Genetic; Fatal Outcome; Forkhead Transcription Factors; Gene Expression Regulation; Genomic Imprinting; HEK293 Cells; Humans; Infant, Newborn; Kruppel-Like Transcription Factors; Nuclear Proteins; Persistent Fetal Circulation Syndrome; Promoter Regions, Genetic; RNA, Long Noncoding; Sequence Deletion; Transcription, Genetic; Zinc Finger Protein Gli2
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