LncRNAs tether transcription factors to enable locus-specific regulation and sustain memory T cell phenotype

LncRNA 束缚转录因子以实现位点特异性调节并维持记忆 T 细胞表型

• 批准号: 9387202
• 负责人: Thomas M. Aune
• 金额: $ 23.7万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387202
• 关键词: Adaptive Immune System; Address; Area; Autoimmune Diseases; Binding; Biology; CCR5 gene; Cell Differentiation process; Cell Lineage; Cells; Chromatin; Chromatin Fiber; Chromatin Loop; Chromosomes; Code; Data; Development; Distal; Enhancers; Epigenetic Process; GATA3 gene; GZMA gene; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genome; Genomic Segment; Genomics; Granzyme; Health Benefit; Human; Immune response; Immunity; Immunologic Memory; Infection; Interferon Type II; Interleukin-2; Interleukin-7; Investigation; Maintenance; Malignant Neoplasms; Mediating; Memory; Modeling; Modification; Molecular Conformation; NF-kappa B; Noise; Phenotype; Process; Property; Proteins; Publishing; RNA; RORA gene; Reading; Regulation; Regulatory Element; Role; T memory cell; TNF gene; Testing; Transcription Process; Untranslated RNA; Vaccine Design; Writing; adaptive immune response; chemokine receptor; cytokine; fight against; gene repression; improved; infancy; migration; pathogen; programs; response; terminally differentiated effector memory (TEM) T cells; transcription factor; Adaptive Immune System; Address; Area; Autoimmune Diseases; Binding; Biology; CCR5 gene; Cell Differentiation process; Cell Lineage; Cells; Chromatin; Chromatin Fiber; Chromatin Loop; Chromosomes; Code; Data; Development; Distal; Enhancers; Epigenetic Process; GATA3 gene; GZMA gene; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genome; Genomic Segment; Genomics; Granzyme; Health Benefit; Human; Immune response; Immunity; Immunologic Memory; Infection; Interferon Type II; Interleukin-2; Interleukin-7; Investigation; Maintenance; Malignant Neoplasms; Mediating; Memory; Modeling; Modification; Molecular Conformation; NF-kappa B; Noise; Phenotype; Process; Property; Proteins; Publishing; RNA; RORA gene; Reading; Regulation; Regulatory Element; Role; T memory cell; TNF gene; Testing; Transcription Process; Untranslated RNA; Vaccine Design; Writing; adaptive immune response; chemokine receptor; cytokine; fight against; gene repression; improved; infancy; migration; pathogen; programs; response; terminally differentiated effector memory (TEM) T cells; transcription factor

Abstract/Summary Immunologic memory is a cardinal feature of the adaptive immune system critical for lifelong immunity to pathogens and, hence, survival of the human species. Memory cells differentiate from naïve precursors by paths that are not entirely clear and acquire phenotypes to allow them to carry out specific functions to provide lifelong immunity. It is generally believed that acquisition of these new phenotypes result from alterations in the transcriptional program by epigenetic modifications at specific target gene loci that enable memory cells to express genes critical for their function. It is easy to see how understanding these responses is important as it could contribute to better vaccine design, enhancement of memory responses to fight against infection or cancers, or faulty regulation of memory responses may contribute to autoimmune diseases, and thus positive or negative regulation of memory responses could have significant health benefits. Activation and repression of transcription of protein-coding genes is key to all facets of biology. Recently the field has learned that much of the genome is transcribed. Two new classes of RNA regulatory elements include long non-coding RNAs (lncRNA) and RNAs transcribed from enhancers (eRNAs). Determining biologic roles of these new classes of RNAs is an active area of investigation still in its infancy. A recent review addressed this question: “Functional roles of enhancer transcription in gene regulation. Three non-exclusive models may underlie the functions of enhancer transcription: the transcription process and enhancer RNAs (eRNAs) are non-functional and are merely transcriptional noise (part A); the act of enhancer transcription mediates function (part B); and genes on the same chromatin fiber (cis), or potentially on other chromosomes (trans), are regulated by an eRNA (part C).” Our central hypothesis is that these RNAs are functional and we propose to address their functions in CD4+ effector memory cells (TEM). We provide preliminary data to support this premise. A corollary is that one mechanism of action of these enhancer-associated RNAs is to bind transcription factors (TFs) and tether them to chromatin. YY1 is one example of a TF that may act in this manner and we provide preliminary data that NF-kB is a second, also supporting our premise. We propose successful completion of studies described herein will not only improve our understanding of this class of RNA molecules but will also improve our understanding of how immunologic memory is maintained. Large numbers of discrete lncRNAs are transcribed from gene loci critical for maintenance of TEM transcriptional programs and are localized at enhancers. The following specific aims are proposed: (1) To determine if IFNG-locus specific enhancer-associated lncRNAs are required for IFNG-AS1, IFNG, IL26, and/or IL22 expression by TEM cells and define epigenetic underpinnings, and (2) To identify biologic functions of additional TEM enhancer associated RNAs and determine if TF binding is a common property.

摘要/摘要 免疫记忆是自适应免疫系统的基本特征，对终身免疫至关重要 病原体，因此，人类物种的生存。记忆细胞通过 尚不完全清晰并获取表型以允许它们执行特定功能以提供的路径 终身免疫。人们普遍认为，这些新表型的获取是由于改变 特定靶基因基因座的表观遗传修饰的转录程序，使记忆细胞能够 表达对其功能至关重要的基因。很容易看出理解这些响应如何很重要 可能有助于更好的疫苗设计，增强记忆反应以抵抗感染或 癌症或记忆反应的调节错误可能导致自身免疫性疾病，因此 或对记忆反应的负调节可能具有重大的健康益处。 蛋白质编码基因转录的激活和表达是生物学所有方面的关键。最近 菲尔德了解到，大部分基因组已被转录。两个新类的RNA调节元素包括 从增强子（ERNAS）转录的长非编码RNA（LNCRNA）和RNA。确定生物学作用 在这些新类别的RNA类中，这是一个仍处于起步阶段的投资领域。最近提出的评论 这个问题：“增强子转录在基因调节中的功能作用。三个非排他性模型 可能是增强子转录功能的基础：转录过程和增强子RNA（ERNAS） 是非功能性的，仅是转录噪声（A部分）；增强子转录培养基的行为 功能（B部分）;以及同一染色质纤维（CI）或其他染色体（反式）上的基因 由ERNA（C部分）调节。”我们的中心假设是这些RNA具有功能性，我们提出了 解决其在CD4+效应器记忆单元（TEM）中的功能。我们提供初步数据来支持这一点 前提。推论是这些增强子相关的RNA的一种作用机理是结合 转录因子（TFS）并将其绑在染色质上。 yy1是可能在此行动的TF的一个例子 我们提供了NF-KB的初步数据，也支持我们的前提。我们建议 成功完成此处描述的研究不仅会改善我们对这类RNA的理解 分子，但也将提高我们对如何维持免疫记忆的理解。数量大 离散lncRNA的转录是从基因基因座转录，对于维持TEM转录程序和 是在增强器的位置。提出了以下特定目的：（1）确定是否特定 IFNG-AS1，IFNG，IL26和/或IL22表达TEM细胞和 定义表观遗传基础和（2）以识别与其他TEM增强子相关的生物学功能 RNA并确定TF结合是否是公共属性。