Document Detail

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.
MedLine Citation:
PMID:  23034409     Owner:  NLM     Status:  MEDLINE    
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.
Przemyslaw Szafranski; Avinash V Dharmadhikari; Erwin Brosens; Priyatansh Gurha; Katarzyna E Kolodziejska; 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 Hustead; Jose Jessurun; Russel Hirsch; David P Witte; Isabelle Maystadt; Neil Sebire; Richard Fisher; Claire Langston; Partha Sen; Paweł Stankiewicz
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  Genome research     Volume:  23     ISSN:  1549-5469     ISO Abbreviation:  Genome Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-06-11     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  9518021     Medline TA:  Genome Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23-33     Citation Subset:  IM    
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
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MeSH Terms
Chromatin / metabolism
Chromosomes, Human, Pair 16 / genetics
CpG Islands
DNA Copy Number Variations*
DNA Methylation*
Enhancer Elements, Genetic
Fatal Outcome
Forkhead Transcription Factors / genetics,  metabolism
Gene Expression Regulation
Genomic Imprinting
HEK293 Cells
Infant, Newborn
Kruppel-Like Transcription Factors / metabolism
Nuclear Proteins / metabolism
Persistent Fetal Circulation Syndrome / diagnosis,  genetics*
Promoter Regions, Genetic
RNA, Long Untranslated / genetics*,  metabolism
Sequence Deletion
Transcription, Genetic
Grant Support
Reg. No./Substance:
0/Chromatin; 0/FOXF1 protein, human; 0/Forkhead Transcription Factors; 0/GLI2 protein, human; 0/Kruppel-Like Transcription Factors; 0/Nuclear Proteins; 0/RNA, Long Untranslated

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