A misplaced IncRNA causes brachydactyly in humans
A misplaced IncRNA causes brachydactyly in humans
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DOI：
10.1172/jci65508
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发表时间：
2012-11-01
影响因子：
15.9
通讯作者：
Baehring, Sylvia
中科院分区：
文献类型：
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作者：
Maass, Philipp G.;Rump, Andreas;Baehring, Sylvia
易位是染色体重排，通常与各种疾病状态和发育障碍有关。我们鉴定了2个因12p染色体不同易位而导致的E型短指畸形（BDE）家族。这两种易位通过破坏顺式调控环境导致甲状旁腺激素样激素（PTHLH）基因下调。通过染色体构象捕获，我们在12q染色体上发现了一个调节因子，它与PTHLH在24.4兆碱基距离上顺式相互作用，与17q染色体上的性别决定区Y-box 9 （SOX9）基因反式相互作用。该元件还含有一个长链非编码RNA （IncRNA）。IncRNA、PTHLH或SOX9的沉默揭示了一种涉及人类表达依赖网络的反馈机制。在BDE患者中，人类IncRNA因染色体关联中断而上调。此外，PTHLH位点的IncRNA占用减少。我们的研究结果记录了我们认为是顺式和反式作用DNA和IncRNA调节反馈元件的新颖之处，这些元件由编码基因相互调节。此外，我们的研究结果为编码IncRNAs的增强子如何影响正常发育中的基因表达提供了系统和组合的观点。
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 (IncRNA). Silencing of the IncRNA, PTHLH, or SOX9 revealed a feedback mechanism involving an expression-dependent network in humans. In the BDE patients, the human IncRNA was upregulated by the disrupted chromosomal association. Moreover, the IncRNA 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 IncRNA regulatory feedback element that is reciprocally regulated by coding genes. Furthermore, our findings provide a systematic and combinatorial view of how enhancers encoding IncRNAs may affect gene expression in normal development.