A misplaced lncRNA causes brachydactyly in humans
Autor: | Atakan Aydin, Sigrid Tinschert, Sigmar Stricker, Sylvia Bähring, Lisanne Schulze, Konrad Platzer, Friedrich C. Luft, Philipp G. Maass, Andreas Rump, Herbert Schulz, Mary B. Goldring |
---|---|
Rok vydání: | 2012 |
Předmět: |
Male
Mice Transgenic Chromosomal translocation Locus (genetics) Biology Translocation Genetic Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Gene silencing Gene Silencing Enhancer Gene 030304 developmental biology Genetics Regulation of gene expression 0303 health sciences Chromosomes Human Pair 12 Brachydactyly Parathyroid Hormone-Related Protein SOX9 Transcription Factor General Medicine medicine.disease Radiography Gene Expression Regulation Genetic Loci Cardiovascular and Metabolic Diseases Commentary Female RNA Long Noncoding Trans-acting 030217 neurology & neurosurgery Chromosomes Human Pair 17 Research Article |
Zdroj: | Journal of Clinical Investigation. 122:3990-4002 |
ISSN: | 0021-9738 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |