Transcriptional regulation of chromatin modifying complexes by noncoding RNAs

非编码RNA对染色质修饰复合物的转录调控

• 批准号: 8165143
• 负责人: Kevin Chun-Kai Wang
• 金额: $ 11.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165143
• 关键词: Adaptor Signaling Protein; Adult; Affect; Anatomy; Animals; Award; Binding; Biology; Body Patterning; Body part; Cell Differentiation process; Cells; Chromatin; Clinical; Collaborations; Complex; Cultured Cells; Dermal; Dermatology; Development; Diagnosis; Disease; Distal; Embryo; Employee Strikes; Epigenetic Process; Epithelial; Ethics; Experimental Designs; Family; Feedback; Fibroblasts; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Histone H3; Homeobox Genes; Homeostasis; Hybrids; Knowledge; Laboratories; Location; Lysine; Maintenance; Mammalian Cell; Mediating; Memory; Mentors; Mesenchymal; Methylation; Modeling; Molecular; Names; Natural regeneration; Organism; Participant; Pattern; Physicians; Positioning Attribute; Process; Proteins; Psoriasis; RNA; RNA Binding; Regulator Genes; Relative (related person); Research; Research Personnel; Resources; Role; Scientist; Scleroderma; Shapes; Site; Skin; Specificity; Structure; Time; To specify; Training; Transcriptional Activation; Transcriptional Regulation; Universities; Untranslated RNA; Work; cellular development; chromatin remodeling; clinically relevant; design; embryonic stem cell; gene repression; in vivo; insight; leukemia; novel; outcome forecast; programs; skin disorder; transcription factor; wound

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.

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，皮肤中特定的位点发育是由相互互相间质相互作用塑造的。发现控制这种相互作用的分子机制对于我们对皮肤病的理解至关重要。 HOX基因是以精致的时间和空间方式调节的转录因子，以指定包括皮肤在内的身体结构的适当位置图案。我们的实验室发现，HOX基因座中的一类新的普遍基因，长的非编码RNA（Lincrnas）在皮肤成纤维细胞中显示出惊人的位点特异性表达。一个位于Hoxa基因座远端的lncRNA称为Hottip，用远端和后体部位的真皮成纤维细胞表示。该RNA的耗竭导致抑制连续的远端HOXA基因的表达，这表明该NCRNA在皮肤远端和表皮中的作用至少通过Hoxa locus的转录激活至少部分地抑制了表皮。 HOTTIP还与WDR5结合，WDR5是染色质修饰复合物混合谱系白血病1（MLL-1）的成分，这表明它可能会通过与MLL-1的相互作用来划分染色体重塑的结构域。该提案的目标的目的是：1）了解热介导的基因调节和转录激活的分子机制，以及2）在体内定义Hottip和其他WDR5结合LNCRNA的功能作用。结果将扩大我们对LNCRNA在皮肤成纤维细胞功能和位置身份中的作用的了解，对理解皮肤病学中临床相关问题的影响，例如伤口再生和特异性疾病表现。 该奖项将使经过皮肤病学培训的医师科学家的主要研究者能够接受皮肤生物学研究的深入培训，并制定自己的独立研究计划。斯坦福大学正在为他提供与该领域专家合作的全部机构支持，丰富的资源和机会。该部门在指导皮肤科医师科学家到独立职位方面拥有强大的田径记录。他将接受道德行为，实验设计和实验室管理的培训，以将他转变为翻译皮肤病学研究中的全日制学术终身任职地位，在那里他将花费90％的时间在研究上和10％的临床活动上。 公共卫生相关性：该提案的重点是在分子层面上理解身体的皮肤如何产生独特的解剖特征。牛皮癣和硬皮病等皮肤的许多疾病都有特定部位的表现。了解为什么发生这种情况的机制对于设计最佳治疗方案具有重要意义。