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A misplaced lncRNA causes brachydactyly in humans

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Item Type:Article
Title:A misplaced lncRNA causes brachydactyly in humans
Creators Name:Maass, P.G. and Rump, A. and Schulz, H. and Stricker, S. and Schulze, L. and Platzer, K. and Aydin, A. and Tinschert, S. and Goldring, M.B. and Luft, F.C. and Bähring, S.
Abstract:Translocations are chromosomal rearrangements that are frequently associated with a variety of disease states and developmental disorders. We identified 2 families with brachydactyly type E (BDE) resulting from different translocations affecting chromosome 12p. Both translocations caused downregulation of the parathyroid hormone-like hormone (PTHLH) gene by disrupting the cis-regulatory landscape. Using chromosome conformation capturing, we identified a regulator on chromosome 12q that interacts in cis with PTHLH over a 24.4-megabase distance and in trans with the sex-determining region Y-box 9 (SOX9) gene on chromosome 17q. The element also harbored a long noncoding RNA (lncRNA). Silencing of the lncRNA, PTHLH, or SOX9 revealed a feedback mechanism involving an expression-dependent network in humans. In the BDE patients, the human lncRNA was upregulated by the disrupted chromosomal association. Moreover, the lncRNA occupancy at the PTHLH locus was reduced. Our results document what we believe to be a novel in cis- and in trans-acting DNA and lncRNA regulatory feedback element that is reciprocally regulated by coding genes. Furthermore, our findings provide a systematic and combinatorial view of how enhancers encoding lncRNAs may affect gene expression in normal development.
Keywords:Brachydactyly, Gene Expression Regulation, Gene Silencing, Genetic Loci, Genetic Translocation, Long Untranslated RNA, Pair 12 Human Chromosomes, Pair 17 Human Chromosomes, Parathyroid Hormone-Related Protein, SOX9 Transcription Factor, Transgenic Mice, Animals, Mice
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:3990-4002
Date:1 November 2012
Official Publication:https://doi.org/10.1172/JCI65508
PubMed:View item in PubMed

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