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

摘要/摘要 免疫记忆是适应性免疫系统的一个基本特征，对终身免疫至关重要。 病原体，因此，人类物种的生存。记忆细胞与幼稚的前体细胞的区别在于 不完全清楚的路径，并获得表型，以允许它们执行特定的功能，以提供 终身豁免权。一般认为，这些新表型的获得是由于 通过在特定的靶基因座上进行表观遗传修饰来转录程序，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反应是多么重要，因为它 可有助于更好的疫苗设计、增强记忆反应以对抗感染或 癌症或记忆反应的错误调节可能会导致自身免疫性疾病，因此是积极的 或者，对记忆反应的负面调节可能会对健康有显著的好处。 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。最近一段时间 菲尔德了解到，基因组的大部分都是转录的。两类新的RNA调节元件包括 长的非编码RNA(LncRNA)和由增强子转录的RNA(ERNAs)。确定生物角色 在这些新的RNA类别中，仍处于初级阶段的是一个活跃的研究领域。最近的一篇评论讨论了 这个问题：“增强子转录在基因调控中的功能作用。三款非专属车型 可能是增强子转录功能的基础：转录过程和增强子RNA(ERNAs) 是不起作用的，仅仅是转录噪音(A部分)；增强子转录的行为调节 功能(B部分)；以及同一染色质纤维上的基因(顺式)，或潜在地在其他染色体上的基因(反式)， 均受环境影响报告书(C部)规管。“我们的中心假设是这些RNA是有功能的，我们提出 探讨它们在CD4+效应记忆细胞中的功能。我们提供了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的一个作用机制是结合 转录因子(TF)，并将其与染色质连接。YY1是一个可以在这个过程中起作用的TF的例子 我们提供的初步数据表明，核因子-kB是第二种，也支持我们的假设。我们建议 成功完成本文所述的研究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。大数字 的离散的lncRNAs是从对维持TEM转录程序至关重要的基因位点转录而来的 都是本地化的增强剂。提出了以下具体目标：(1)确定IFNG基因座是否具有特异性 表达IFNG-AS1、IFNG、IL26和/或IL22需要增强子相关的lncRNA 定义表观遗传学基础，以及(2)鉴定额外的透射电子显微镜增强子相关的生物功能 RNA，并确定Tf结合是否是常见属性。

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.