Transcriptional regulation of chromatin modifying complexes by noncoding RNAs

描述（由申请人提供）：许多皮肤疾病具有独特的解剖表现，对诊断、预后和治疗具有重要意义。众所周知，皮肤的部位特异性发育是由相互的上皮-间质相互作用形成的。发现控制这种相互作用的分子机制对我们了解皮肤病至关重要。HOX基因是一种转录因子，以一种精致的时间和空间方式调节，以指定包括皮肤在内的身体结构的适当位置模式。我们的实验室发现，HOX基因座中的一类新的普遍基因，长链非编码rna （lincRNAs）在皮肤成纤维细胞中表现出惊人的位点特异性表达。一个位于HOXA位点远端的lncRNA，称为HOTTIP，在远端和后体部位的真皮成纤维细胞中表达。该RNA的缺失会导致邻近远端HOXA基因的表达受到抑制，这表明该ncRNA至少在一定程度上通过对HOXA位点的转录激活，参与远端真皮和表皮的模式形成。HOTTIP还可以结合WDR5，这是染色质修饰复合物混合谱系白血病-1 （MLL-1）的一个组成部分，表明它可能通过与MLL-1的相互作用来划分染色体重塑的区域。本课题的目标是：1)了解HOTTIP介导的基因调控和转录激活的分子机制；2)明确HOTTIP和其他wdr5结合lncrna在体内分化和发育模式中的功能作用。该结果将扩展我们对lncRNAs在皮肤成纤维细胞功能和位置识别中的作用的认识，并对理解皮肤病学中的临床相关问题（如伤口再生和部位特异性疾病表现）具有重要意义。该奖项将使首席研究员，一位受过皮肤科训练的内科科学家，能够接受皮肤生物学研究方面的强化培训，并发展自己的独立研究项目。斯坦福大学正在为他提供全面的制度支持、广泛的资源以及与该领域专家合作的机会。该系在指导皮肤科内科科学家独立担任职务方面有着良好的记录。他将接受伦理行为、实验设计和实验室管理方面的培训，以使他成为转化皮肤病学研究的全职学术终身职位，他将把90%的时间用于研究，10%用于临床活动。

DESCRIPTION (provided by applicant): Many diseases of the skin have unique anatomic manifestations that have important implications for diagnosis, prognosis, and treatment. It is well known that site- specific development in the skin is shaped by reciprocal epithelial-mesenchymal interactions. Discovering the molecular mechanisms that govern this interaction is vital to our understanding of skin disease. The HOX genes are transcription factors that are regulated in an exquisite temporal and spatial manner to specify proper positional patterning of body structures including the skin. Our laboratory has discovered that a new class of pervasive genes, long noncoding RNAs (lincRNAs), in the HOX loci show striking site-specific expression in skin fibroblasts. One lncRNA located at the distal end of the HOXA locus, termed HOTTIP, is expressed in dermal fibroblasts from distal and posterior body sites. Depletion of this RNA leads to a suppression of expression of contiguous distal HOXA genes, suggesting a role for this ncRNA in distal dermal and epidermal patterning at least in part through transcriptional activation of the HOXA locus. HOTTIP also binds to WDR5, a component of the chromatin modifying complex Mixed- Lineage Leukemia-1 (MLL-1), suggesting it may demarcate domains of chromosomal remodeling via interactions with MLL-1. The goals of this proposal are aimed at: 1) understanding the molecular mechanisms of HOTTIP-mediated gene regulation and transcriptional activation, and 2) defining the functional role for HOTTIP and other WDR5-binding lncRNAs in differentiation and developmental patterning in vivo. The results will expand our knowledge of the role of lncRNAs in skin fibroblast function and positional identity with implications for understanding clinically relevant issues in dermatology such as wound regeneration and site-specific disease manifestations. This award will enable the principle investigator, a dermatology trained physician-scientist, to receive intensive training in skin biology research and develop his own independent research program. Stanford University is providing him full institutional support, extensive resources, and opportunity for collaborations with experts in the field. The department has a strong track-record in mentoring dermatology physician-scientists to independent positions. He will be trained in ethical conduct, experimental design, and laboratory management to transition him to a full-time academic tenure-track position in translational dermatology research where he will spend 90% of his time on research and 10% on clinical activities. PUBLIC HEALTH RELEVANCE: This proposal is focused on understanding at the molecular level how skin from different parts of the body develops unique anatomical features. Many diseases of the skin, such as psoriasis and scleroderma, have site-specific manifestations. Understanding the mechanism of why this occurs has important implications for designing the best treatment options.