A Gene Regulatory Network Controlled by Transcription Factor ZBTB38 in RA

RA中转录因子ZBTB38控制的基因调控网络

基本信息

批准号：
8569609
负责人：
Tibor Attila Rauch
金额：
$ 19.51万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8569609
关键词：
Affect Animal Model Area Arthritis Autoimmune Process B-Lymphocytes BTB/POZ Domain Binding Sites Biological Markers Cartilage Cell Culture Techniques Cells ChIP-seq Clinical Management Code Cytokine Network Pathway DNA Methylation DNA Sequence Data Development Disease Disease Progression Drug Targeting Environmental Risk Factor Epigenetic Process Etiology Event Gene Activation Gene Expression Genes Genetic Genetic Transcription Genome Goals Homologous Gene Human Human Genome Immune Individual Inflammatory Investigation Joints Lead Link Lymphocyte Maps Minor Molecular Monitor Mus Nature Pathogenesis Pathology Pathway interactions Patients Pattern Peripheral Peripheral Blood Lymphocyte Phenotype Play Pollution Population Process Proteins Proteoglycan RNA Sequences Receptor Signaling Regulation Regulator Genes Research Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis Risk Factors Role Sampling Signal Transduction Pathway Smoking Techniques Testing Therapeutic Time Toll-like receptors Transcriptional Regulation Up-Regulation Zinc Fingers autoimmune arthritis base cell type chemokine cytokine epigenome gene function gene interaction genome wide association study genome-wide histone modification insight lymphoblastoid cell line member novel peripheral blood promoter public health relevance receptor research study transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA)-associated cytokine networks, cellular receptors, and signal transduction pathways have been fairly well characterized. However, gene regulatory networks that may drive and amplify inflammatory processes in RA have not been explored. Using mice with cartilage proteoglycan (PG)-induced arthritis (an autoimmune animal model of RA), we detected arthritis-specific epigenetic changes in B lymphocytes, which caused markedly upregulated expression of the gene encoding the "zinc finger and BTB domain containing 38" (ZBTB38) transcription factor. The ZBTB38 gene was similarly upregulated in lymphocytes of the majority of tested RA patients as compared to healthy individuals. We also found that ZBTB38 could facilitate its own transcription, and stimulate the expression of a number of other genes including those coding for transcription factors, pro-inflammatory cytokines, as well as chemokine and Toll-like receptors. Intriguingly, many of the gene products affected by ZBTB38's transcription factor activity have been implicated in RA pathogenesis. Our preliminary data argue for the involvement of ZBTB38 in an intricate gene regulatory network that controls inflammatory/autoimmune processes in RA. We will identify the members of this network and delineate their interactions in lymphocytes from arthritic mice and from patients with RA. In addition, we will further investigate arthritis-relate epigenetic events in selected RA patients. The proposed project should help in exploring genetic/epigenetic mechanisms involved in the regulation of a major RA- associated inflammatory pathway, and may also identify genes as novel biomarkers and drug targets for RA.

描述（由申请人提供）：类风湿性关节炎（RA）相关的细胞因子网络、细胞受体和信号转导途径已经得到相当好的表征。然而，尚未探索可能驱动和放大 RA 炎症过程的基因调控网络。使用软骨蛋白多糖 (PG) 诱导的关节炎（RA 的自身免疫动物模型）小鼠，我们检测到 B 淋巴细胞中关节炎特异性表观遗传变化，这导致编码“锌指和包含 38 的 BTB 结构域”的基因表达显着上调(ZBTB38)转录因子。与健康个体相比，大多数测试的 RA 患者的淋巴细胞中 ZBTB38 基因同样上调。我们还发现 ZBTB38 可以促进其自身转录，并刺激许多其他基因的表达，包括编码转录因子、促炎细胞因子以及趋化因子和 Toll 样受体的基因。有趣的是，许多受 ZBTB38 转录因子活性影响的基因产物与 RA 发病机制有关。我们的初步数据表明 ZBTB38 参与了控制 RA 炎症/自身免疫过程的复杂基因调控网络。我们将鉴定该网络的成员，并描述它们在关节炎小鼠和类风湿性关节炎患者的淋巴细胞中的相互作用。此外，我们将进一步研究选定的 RA 患者中与关节炎相关的表观遗传事件。拟议的项目应有助于探索参与主要 RA 相关炎症途径调节的遗传/表观遗传机制，并且还可以将基因识别为 RA 的新型生物标志物和药物靶点。