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学表现，对诊断、预后和治疗具有重要意义。众所周知，皮肤中的位点特异性发育是由上皮-间充质相互作用形成的。发现控制这种相互作用的分子机制对我们理解皮肤病至关重要。HOX基因是转录因子，其以精确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图案。我们的实验室已经发现，一类新的普遍基因，长非编码RNA（lincRNA），在HOX基因座显示出惊人的位点特异性表达在皮肤成纤维细胞。位于HOXA基因座远端的一种lncRNA，称为HOTTIP，在来自身体远端和后部部位的真皮成纤维细胞中表达。这种RNA的消耗导致连续远端HOXA基因表达的抑制，表明这种ncRNA至少部分通过HOXA基因座的转录激活在远端真皮和表皮图案形成中的作用。HOTTIP还结合染色质修饰复合物混合谱系白血病-1（MLL-1）的组分WDR 5，表明其可以通过与MLL-1的相互作用划分染色体重塑的结构域。该提案的目标是：1）理解HOTTIP介导的基因调控和转录激活的分子机制，以及2）定义HOTTIP和其他WDR 5结合lncRNA在体内分化和发育模式中的功能作用。这些结果将扩大我们对lncRNA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（如伤口再生和特定部位疾病表现）产生影响。 该奖项将使主要研究者，皮肤科训练有素的医生，科学家，接受皮肤生物学研究的强化培训，并制定自己的独立研究计划。斯坦福大学正在为他提供全面的机构支持，广泛的资源和与该领域专家合作的机会。该部门在指导皮肤科医生-科学家独立职位方面有着良好的记录。他将接受道德行为，实验设计和实验室管理方面的培训，以使他在转化皮肤病学研究中获得全职学术终身职位，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.