Gene Regulation In The Immune System

免疫系统中的基因调控

• 批准号: 7333997
• 负责人: Keiko Ozato
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7333997
• 关键词: Gene; Regulation; Immune; System

This section is interested in transcription factors that regulate the development of the immune system. IRF-8/ICSBP, a DNA specific transcription factor is essential for the development of macrophages and dendritic cells. In addition to their development, IRF-8 controls the expression of interferons and the IL-12 cytokine in these cells, thereby playing a critical role in the establishment of innate immunity. To address the mechanism of IRF-8 action, we performed photobleaching experiments. We show that IRF-8 is moving rapidly in the nucleus and scanning the entire genome by transiently binding to chromatin in macrophages and DCs. Further analysis showed that IRF-8 chromatin interactions are regulated by external cytokine signaling. This study opened a new way to study transcription in living immune cells. Another model we investigate deals with a bromodomain protein Brd4. This protein binds to acetylated chromatin and associates with chromosomes during mitosis. Brd4 is thought to play a role in epigenetic memory. We found that Brd4 interacts with P-TEFb, a Cdk9/CyclinT heterodimer that is essential for RNA polymerase II transcriptional elongation. By chromatin immunoprecipitation analysis of the HIV-1LTR reporter, we provided evidence that Brd4 recruits P-TEFb to the promoter to stimulate transcription. These studies have unraveled a previously unknown role for Brd4 in transcription.

本节对调节免疫系统发展的转录因子感兴趣。 IRF-8/ICSBP，DNA特异性转录因子对于巨噬细胞和树突状细胞的发展至关重要。除了其发育外，IRF-8还控制着这些细胞中干扰素和IL-12细胞因子的表达，从而在建立先天免疫力中起着至关重要的作用。为了解决IRF-8动作的机制，我们进行了光漂白实验。我们表明，IRF-8在核中迅速移动，并通过在巨噬细胞和DC中瞬时与染色质结合来扫描整个基因组。进一步的分析表明，IRF-8染色质相互作用受外部细胞因子信号传导调节。这项研究开辟了一种研究生物免疫细胞转录的新方法。我们研究的另一个模型处理溴结构域蛋白BRD4。该蛋白质与乙酰化染色质结合，并在有丝分裂过程中与染色体相关。 BRD4被认为在表观遗传记忆中起作用。我们发现BRD4与P-TEFB相互作用，P-TEFB是RNA聚合酶II转录伸长至关重要的CDK9/CYCLINT异二聚体。通过对HIV-1LTR记者的染色质免疫沉淀分析，我们提供了证据表明BRD4将P-TEFB募集到启动子启动子以刺激转录。这些研究揭示了BRD4在转录中的先前未知作用。