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

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/概要 免疫记忆是适应性免疫系统的一个重要特征，对于终身免疫至关重要。 病原体，因此，人类物种的生存。记忆细胞通过以下方式与幼稚前体细胞分化： 路径并不完全清楚，并获得表型，使他们能够执行特定的功能，以提供 终身免疫一般认为，这些新表型的获得是由于以下基因的改变所致： 通过特定靶基因位点的表观遗传修饰进行转录编程，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反应是多么重要，因为它 可以有助于更好的疫苗设计，增强记忆反应以对抗感染， 癌症或记忆反应调节错误可能会导致自身免疫性疾病，因此呈阳性 或负调节记忆反应可能有显著的健康益处。 蛋白质编码基因转录的激活和抑制是生物学各个方面的关键。最近 菲尔德已经了解到基因组的大部分是转录的。两类新的RNA调控元件包括 长非编码RNA（lncRNA）和增强子转录的RNA（eRNA）。确定生物作用 这些新类型的RNA的研究是一个活跃的研究领域，仍处于起步阶段。最近的一次审查讨论了 这个问题：“增强子转录在基因调控中的功能作用。三种非独占模式 可能是增强子转录功能的基础：转录过程和增强子RNA（eRNA） 是非功能性的，仅仅是转录噪音（A部分）;增强子转录的行为介导 功能（部分B）;以及在同一染色质纤维上的基因（顺式），或可能在其他染色体上的基因（反式）， 由eRNA调控（C部分）。我们的中心假设是这些RNA是功能性的，我们建议 以解决其在CD 4+效应记忆细胞（TEM）中的功能。我们提供初步数据来支持这一点 前提一个推论是，这些增强子相关RNA的一种作用机制是结合 转录因子（TF），并将它们拴在染色质上。YY 1是可以在此情况下起作用的TF的一个示例。 方式，我们提供的初步数据，NF-κ B是第二，也支持我们的前提。我们提出 本文所述研究的成功完成不仅将提高我们对这类RNA的理解， 分子，但也将提高我们对免疫记忆是如何维持的理解。大量 的离散lncRNA从对维持TEM转录程序至关重要的基因位点转录， 位于增强子上具体目的如下：（1）确定IFNG位点特异性 增强子相关的lncRNA是TEM细胞表达IFNG-AS 1、IFNG、IL 26和/或IL 22所必需的， 定义表观遗传基础，和（2）确定额外的TEM增强子相关的生物学功能 RNA和确定TF结合是否是一个共同的属性。