Characterization of Regulated Intron Retention in T Cell Activation

T 细胞激活中受调控内含子保留的表征

• 批准号: 8882260
• 负责人: Robert G. Hawley
• 金额: $ 19.06万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882260
• 关键词: 3' Untranslated Regions; Alternative Splicing; Attention; Biological Models; CD4 Positive T Lymphocytes; CD8B1 gene; ChIP-seq; Characteristics; Chromatin; Computer Analysis; Coupled; Coupling; Dimensions; Disease; Drug Targeting; Epigenetic Process; Eukaryota; Future; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Health; Histones; Human; Hypersensitivity; Immune System Diseases; Immune response; Immune system; Immunologic Deficiency Syndromes; Information Systems; Introns; Maps; Messenger RNA; Molecular; Mus; Pathway interactions; Play; Polyadenylation; Post-Transcriptional Regulation; Prevalence; Process; Proxy; Public Health; RNA Polymerase II; RNA Processing; RNA Splicing; Regulation; Role; Septic Shock; Site; System; T-Cell Activation; T-Lymphocyte; Therapeutic; Transcription Factor AP-1; Transcriptional Regulation; Work; abstracting; adaptive immunity; cell type; computer framework; epigenome; epigenomics; genome-wide; human data; insight; interest; mRNA Transcript Degradation; novel; programs; response; transcriptome sequencing; transcriptomics

DESCRIPTION (provided by applicant): Project Summary/Abstract T cell activation is an essential step in immune response and abnormalities result in pathogenic conditions, including immunodeficiency, septic shock and auto-immune diseases. The activation process involves a coordinated program of gene expression regulations at both transcriptional and post-transcriptional levels. Our preliminary work in human CD4+ T cells demonstrated that regulated intron retention coupled with mRNA degradation may serve as a novel post- transcriptional regulatory mechanism underlying T cell activation. Intron retention is one of the key forms of alternative splicing in eukaryotes. However, its functional involvement in gene regulation has not been well explored. We propose to bridge the gap by accomplishing the following specific aims. Aim 1: Characterize the defining features of intron retention. Our preliminary results showed that intron retention is gene- and intron- specific. Intron-retained genes are associated with a unique epigenetic state. The sequence and chromatin signatures will help pave the path for future mechanistic studies of IR. We also propose to examine the conservation of regulated intron retention across cell-types and species. To understand the extent of its conservation, we propose to collect transcriptomic profile (RNA-Seq), genome-wide occupancy of RNA Polymerase II (ChIP-Seq), as well as other epigenomic data for human CD8+ T cells and mouse CD4+ T cells. An Integrated computational analysis will be used to assess the prevalence of intron retention and its functional role in immune system activation. Collectively, data from these systems will provide novel insights into the core features of intron retention and its regulation at the sequence, epigenetic and network level. Aim 2: Understand the connection of regulated intron retention with other modes of gene regulation. To gain a comprehensive understanding of the regulation of the activation process, it is important to examine how they work in concert. We will determine the division of labor between transcriptional regulation, regulated intron retention, and shortening of 3' untranslated region, another mode of post-transcriptional regulation prominent in the T cell activation process. The proposed work promises to yielding clues to the molecular mechanism of intron retention and its regulation, and opening up a new dimension in our understanding of the regulation of adaptive immune response. In addition, we anticipate the integrative computational frameworks developed in this project to be useful for studying intron retention in other systems.

描述（由申请人提供）：项目摘要/摘要 T 细胞激活是免疫反应的重要步骤，异常会导致致病性疾病，包括免疫缺陷、感染性休克和自身免疫性疾病。激活过程涉及转录和转录后水平上基因表达调控的协调程序。我们在人 CD4+ T 细胞中的初步工作表明，受调节的内含子保留与 mRNA 降解相结合可能作为 T 细胞激活的一种新型转录后调节机制。内含子保留是真核生物中选择性剪接的关键形式之一。然而，其在基因调控中的功能尚未得到很好的探索。我们建议通过实现以下具体目标来缩小差距。目标 1：表征内含子保留的定义特征。我们的初步结果表明，内含子保留是基因和内含子特异性的。内含子保留基因与独特的表观遗传状态相关。序列和染色质特征将有助于为未来 IR 的机制研究铺平道路。我们还建议检查跨细胞类型和物种的受调控内含子保留的保守性。为了了解其保守程度，我们建议收集转录组谱 (RNA-Seq)、RNA 聚合酶 II 的全基因组占用率 (ChIP-Seq)，以及人类 CD8+ T 细胞和小鼠 CD4+ T 细胞的其他表观基因组数据。综合计算分析将用于评估内含子保留的普遍性及其在免疫系统激活中的功能作用。总的来说，来自这些系统的数据将为内含子保留的核心特征及其在序列、表观遗传和网络水平上的调控提供新的见解。目标 2：了解受调控的内含子保留与其他基因调控模式的联系。为了全面了解激活过程的调节，重要的是检查它们如何协同工作。我们将确定转录调控、受调控的内含子保留和 3' 非翻译区缩短之间的分工，这是 T 细胞激活过程中突出的另一种转录后调控模式。这项工作有望为内含子保留及其调节的分子机制提供线索，并为我们理解适应性免疫反应的调节开辟新的维度。此外，我们预计该项目中开发的综合计算框架可用于研究其他系统中的内含子保留。

项目成果

A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex.

• DOI: 10.1101/gad.268797.115
• 发表时间: 2016-01-15
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Starnes LM;Su D;Pikkupeura LM;Weinert BT;Santos MA;Mund A;Soria R;Cho YW;Pozdnyakova I;Kubec Højfeldt M;Vala A;Yang W;López-Méndez B;Lee JE;Peng W;Yuan J;Ge K;Montoya G;Nussenzweig A;Choudhary C;Daniel JA
• 通讯作者: Daniel JA

MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis.

• DOI: 10.1093/nar/gkx234
• 发表时间: 2017-06-20
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Lai B;Lee JE;Jang Y;Wang L;Peng W;Ge K
• 通讯作者: Ge K

Global intron retention mediated gene regulation during CD4+ T cell activation.

CD4( ) T 细胞激活过程中全局内含子保留介导的基因调控

• DOI: 10.1093/nar/gkw591
• 发表时间: 2016-08-19
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Ni T;Yang W;Han M;Zhang Y;Shen T;Nie H;Zhou Z;Dai Y;Yang Y;Liu P;Cui K;Zeng Z;Tian Y;Zhou B;Wei G;Zhao K;Peng W;Zhu J
• 通讯作者: Zhu J

Correlating Chemical Sensitivity with Low Level Activation of Mechanotransduction Pathways in Hematologic Malignancies.

• DOI: 10.14218/erhm.2017.00022
• 发表时间: 2017-07
• 期刊: Exploratory research and hypothesis in medicine
• 作者: Hawley RG