| Small non-coding differentially-methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder. | |
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MedLine Citation:
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PMID: 23034409 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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An unanticipated and tremendous amount of the non-coding sequences of the human genome are transcribed. Long non-coding RNAs (lncRNAs) constitute a significant fraction of non-protein coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small non-coding 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 to FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete two 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 GLI and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomenon and potentially cause many disorders of human development. |
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Authors:
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Przemyslaw Szafranski; Avinash V Dharmadhikari; Erwin Brosens; Priyatansh Gurha; Katarzyna E Kolodziejska; Zhishuo Ou; Piotr Dittwald; Tadeusz Majewski; K Naga Mohan; Bo Chen; Richard 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; Pawel Stankiewicz |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-3 |
Journal Detail:
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Title: Genome research Volume: - ISSN: 1549-5469 ISO Abbreviation: Genome Res. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-4 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9518021 Medline TA: Genome Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Baylor College of Medicine; |
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