Szafranski, P;
Dharmadhikari, AV;
Brosens, E;
Gurha, P;
Kolodziejska, KE;
Zhishuo, O;
Dittwald, P;
... Stankiewicz, P; + view all
(2013)
Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.
Genome Research
, 23
(1)
23 - 33.
10.1101/gr.141887.112.
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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.
| Type: | Article |
|---|---|
| Title: | Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1101/gr.141887.112 |
| Publisher version: | http://dx.doi.org/10.1101/gr.141887.112 |
| Language: | English |
| Additional information: | This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits use, distribution, and reproduction in any medium, provided that that reuse is restricted to non-commercial purposes, i.e. research or educational use, and the original work is properly cited. PMCID: PMC3530681 |
| Keywords: | 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 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1377881 |
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