Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.
Genome Res
; 23(1): 23-33, 2013 Jan.
Article
em En
| MEDLINE
| ID: mdl-23034409
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Síndrome da Persistência do Padrão de Circulação Fetal
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Metilação de DNA
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Variações do Número de Cópias de DNA
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RNA Longo não Codificante
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Humans
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Newborn
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article