Defining the Transcriptional Regulation and Genomic Organization of FAIM3 and PIGR, Human Ig Receptors Involved in Immunity, Auto-Immune Disease, and Lymphoma

定义 FAIM3 和 PIGR、参与免疫、自身免疫性疾病和淋巴瘤的人类 Ig 受体的转录调控和基因组组织

• 批准号: 9395470
• 负责人: Jared Andrews
• 金额: $ 3万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395470
• 关键词: 3-Dimensional; Address; Affinity; Alpha Cell; Autoimmune Diseases; Autoimmunity; B-Cell Lymphomas; B-Lymphocytes; Binding; Biological Assay; CRISPR/Cas technology; Cell Lineage; Cells; ChIP-seq; Chromatin; Code; Complementary DNA; Control Locus; DNA; DNA Sequence Alteration; Data; Development; Disease; Elements; Enhancers; Epigenetic Process; Epithelial Cells; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome; Genomics; Human; IgA receptor; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulin M; Individual; Infection; Inherited; Link; Luciferases; Lymphocyte; Lymphoid Cell; Lymphoma; Malignant Neoplasms; Malignant lymphoid neoplasm; Measures; Mediating; Molecular Profiling; Mutation; Oncogene Deregulation; Pathogenesis; Positioning Attribute; Precipitation; Proteins; RNA Splicing; Recurrence; Regulation; Regulator Genes; Regulatory Element; Role; Small Interfering RNA; Specificity; Structure; Surface; Testing; Transcript; Transcriptional Regulation; Untranslated RNA; Variant; cell type; cellular development; chromosome conformation capture; experience; experimental study; genetic profiling; immune function; immunoglobulin receptor; knock-down; leukemia/lymphoma; metaplastic cell transformation; novel; overexpression; pathogen; receptor; three dimensional structure; tool; transcription factor; transcriptome

ABSTRACT A fundamental outstanding question in cellular development remains how epigenetic mechanisms of gene regulation are coordinated during development and their role in disease. Genome structure and topology, local chromatin landscape, and non-coding RNAs all contribute to epigenetic transcriptional regulation. Moreover, alterations in these elements or factors can perturb gene expression and promote disease pathogenesis, as shown for B cell lymphoma (Koues et al, Immunity 2015). While the general principles of these mechanisms are widely accepted, the specific identity and interplay of these elements at individual gene loci is largely unknown. Therefore, the proposed studies will define regulatory interactions at a single locus containing two genes that are essential for normal immune function and, when deregulated, promote auto-immunity or cancer. FAIM3 (TOSO, FCMR) is an IgM receptor expressed in innate and adaptive immune cells, and PIGR encodes the IgA receptor and secreted IgA in mucosal epithelial cells. Importantly, preliminary studies show that regulatory elements and a lncRNA in this locus are deregulated in B cell lymphomas and leukemia. By elucidating the regulatory mechanisms that control expression of these genes in a cell-specific manner, the key elements necessary for lineage specificity and how these regulatory mechanisms are corrupted in lymphoid cancers will be revealed. Aim 1 will define the genomic organization and 3-dimensional structure of the locus. In addition, Aim 1 studies will determine the contribution of regulatory elements to maintaining this structure and transcriptional control of FAIM3, PIGR, and neighboring genes. Aim 2 will elucidate the transcription factors that serve as key regulators of FAIM3 and PIGR and determine how genetic polymorphisms and mutations alter this regulation through perturbation of transcription factor binding. Aim 3 will characterize a novel long non-coding RNA, confirming its full sequence, verifying its exonic structure, and determining whether it contributes to the transcriptional control of FAIM3 or PIGR. Upon completion of these studies, the regulatory elements and mechanisms that control the cell-specific expression of FAIM3 and PIGR will be defined, as will how these genes are altered in lymphoid cancer. The impact of these studies will reach beyond a single gene locus, by providing a window into the intricate interplay of epigenetic and genetic mechanisms of gene regulation and deregulation in normal development and cancer.

抽象的 细胞发育中一个基本的悬而未决的问题仍然是基因的表观遗传机制如何 发育过程中的调节及其在疾病中的作用是协调的。基因组结构和拓扑，局部 染色质景观和非编码 RNA 都有助于表观遗传转录调控。而且， 这些元素或因素的改变可以扰乱基因表达并促进疾病发病机制，如 显示 B 细胞淋巴瘤（Koues 等人，Immunity 2015）。虽然这些机制的一般原理 被广泛接受，这些元素在各个基因位点的具体身份和相互作用在很大程度上是 未知。因此，拟议的研究将定义包含两个基因座的监管相互作用 对正常免疫功能至关重要的基因，当失调时，会促进自身免疫或癌症。 FAIM3（TOSO、FCMR）是先天性和适应性免疫细胞中表达的 IgM 受体，PIGR 编码 粘膜上皮细胞中的 IgA 受体并分泌 IgA。重要的是，初步研究表明 该位点的调节元件和 lncRNA 在 B 细胞淋巴瘤和白血病中失调。经过 阐明以细胞特异性方式控制这些基因表达的调控机制，关键 谱系特异性所必需的元素以及这些调节机制如何在淋巴中被破坏 癌症将被揭露。目标 1 将定义基因座的基因组组织和 3 维结构。 此外，目标 1 研究将确定监管要素对维持这种结构的贡献 FAIM3、PIGR 和邻近基因的转录控制。目标 2 将阐明转录 作为 FAIM3 和 PIGR 关键调节因子并决定遗传多态性和 突变通过干扰转录因子结合来改变这种调节。目标 3 将描述 新型长非编码RNA，确认其全序列，验证其外显子结构，并确定 它是否有助于 FAIM3 或 PIGR 的转录控制。完成这些研究后， 控制 FAIM3 和 PIGR 细胞特异性表达的调控元件和机制将被 定义，以及这些基因在淋巴癌中如何改变。这些研究的影响将超越 单个基因位点，通过提供一个窗口来了解表观遗传和遗传机制的复杂相互作用 正常发育和癌症中的基因调控和失调。