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

描述(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一种新机制。具体地说，这些研究集中在一种新的调控RNA-胚胎腹前脑(EVF)。目前，人们对发育中的非编码RNA(NcRNAs)知之甚少。EVF ncRNAs是第一个被发现的影响特定增强子转录活性的发育调节ncRNAs。EVF ncRNAs也是第一个与含有同源异型盒的转录因子相互作用和复合的ncRNAs。因此，这项拟议的研究将是第一次调查发育调节的ncRNA依赖的增强子活性调节在体内的作用。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，这将具有远远超出开发研究的应用范围。功能调控RNA被认为与Prader Willi综合征、DiGeorge综合征、Beckwith-Wiedeman综合征、脊髓小脑性共济失调8型和钟状核发育不良有关，因此拟议的实验将与理解这些疾病的原因有关。我们发现EVF ncRNAs调节含有DLX 5和6同源框的转录因子的表达。我们还发现EVF基因与DLX 5/6基因在小鼠和人类6号和7号染色体之间的同步区分别重叠。DLX 5/6基因和小鼠6号染色体这一特定区域的重要性从最近的一项研究中清楚地看出，DLX 5/6在小鼠中的缺失与人类遗传病-分裂-手-分裂脚畸形(SHFM)相似。因此，对DLX5/6调控的研究对于了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具有重要意义。

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.