A Novel ncRNA involved in the Regulation of Dlx 5/6

描述（由申请人提供）：这项工作的主要目的是研究发育过程中基因调控的新机制。具体来说，这些研究集中在一种新的调控RNA，胚胎腹前脑（Evf）。目前，对发育中的非编码RNA（ncRNA）知之甚少。Evf ncRNA是第一个被发现的影响特异性增强子转录活性的发育调节ncRNA。Evf ncRNA也是第一个显示与含同源框的转录因子合作和复合的ncRNA。因此，拟议的研究将是第一个调查体内作用的发育调节ncRNA依赖性调节增强子活性。如果ncRNA介导的增强子调控被证明是一种常见的转录调控机制，这将具有远远超出发育研究的应用。功能性调节RNA被认为参与Prader Willi综合征、diGeorge综合征、Beckwith-Wiedeman综合征、脊髓小脑共济失调8型和Campomelic发育不良，因此所提出的实验将与理解这些疾病是如何引起的有关。我们表明，Evf ncRNA调节的DLX 5和6同源框含有转录因子的表达。我们还表明，Evf基因重叠与Dlx 5/6基因在一个区域的同线性之间的小鼠和人类染色体6和7，分别。Dlx 5/6基因和小鼠6号染色体的这一特定区域的重要性从最近的证明中清楚地表明，小鼠中Dlx 5/6的缺失与人类遗传疾病裂手裂足畸形（SHFM）表型相似。因此，研究Dlx 5/6的调节对于理解颅面和肢体发育以及由这些过程的改变引起的人类疾病将是重要的。

DESCRIPTION (provided by applicant): The major purpose of this work is to investigate a novel mechanism of gene regulation during development. Specifically, these studies focus on a novel regulatory RNA, embryonic ventral forebrain (Evf). Presently, very little is known about non-coding RNAs (ncRNAs) in development. Evf ncRNAs are the first developmentally regulated ncRNAs to be discovered that affect the transcriptional activity of a specific enhancer. Evf ncRNAs are also the first ncRNAs shown to cooperate and complex with a homeobox-containing transcription factor. The proposed studies would therefore be the first to investigate the in vivo role of developmentally regulated ncRNA-dependent modulation of enhancer activity. If ncRNA-mediated enhancer regulation proves to be a common transcriptional regulatory mechanism, this will have applications reaching far beyond the study of development. Functional regulatory RNAs are thought to be involved in Prader Willi Syndrome, diGeorge Syndrome, Beckwith-Wiedeman syndrome, Spinocerebellar ataxia type 8, and campomelic dysplasia, and thus the proposed experiments will be relevant to understanding how these diseases are caused. We show that Evf ncRNAs regulate the expression of the Dlx 5 and 6 homeobox-containing transcription factors. We also show that the Evf gene overlaps with the Dlx 5/6 genes in a region of synteny between the mouse and human chromosomes 6 and 7, respectively. The importance of the Dlx 5/6 genes and this particular region of mouse chromosome 6 is clear from the recent demonstration that the deletion of Dlx 5/6 in the mouse phenocopies the human genetic disease, split-hand-split foot malformation (SHFM). Therefore, investigation of Dlx 5/6 regulation will be important to understanding craniofacial and limb development as well as a human disease that results from alterations in these processes.