Gene Regulation In The Immune System

免疫系统中的基因调控

• 批准号: 6822779
• 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/6822779
• 关键词: antisense nucleic acid; cell differentiation; cell growth regulation; cell proliferation; chromatin; cytokine; dendritic cells; gene expression; genetic regulation; immunoregulation; macrophage; microarray technology; oncoproteins; protein structure function; transcription factor

This section is interested in transcription factors that regulate the development of the immune system. We previously isolated ICSBP/IRF-8, a DNA specific transcription factor expressed in hematopoietic cells and showed that it regulates the development of bone marrow progenitor cells to generate macrophages and granulocytes. We also showed that introduction of ICSBP rescues normal growth and differentiation of these cells in ICSBP-null progenitors. It can also rescue the development and maturation of dendritic cells (DCs), cells important for host defense. ICSBP-null mice are imunodeficient and lack the capacity for innate immunity, because these mice do not express IL-12p40,and interferons (tyoe I IFNs. Although these cytokines are not produced in ICSBP-/- macrophages and DCs, reintroduction of ICSBP can fully restore the cytokine production. By DNA microarray analysis with 15,000 murine cDNAs, we have begun to identify additional target genes that are directly regulated by ICSBP. About 50 known and unknown genes are found to be either increased or decreased following ICSBP expression, some of which are known to be important for macrophage/DC function. Studies of target promoters and the chromatin status of ICSBP-null cells suggest that this factor regulates gene expression not only by controlling target promoters, but regulating the activity of chromatin. We study the role of chromatin from another perspective, and characterize a bromodomain protein Brd4. Brd4 is a novel member of the conserved BET family, that contains a motif indicative of interaction with chromatin. We showed that it associates with mitotic chromosomes, consistent with a strong affinity for chromatin. Recent FRET and FLIP analyses suggest that Brd4 and a related protein interact with acetylated histones in living cells. By an over-expression strategy, Brd4 is found to regulate cell growth. We show that this growth regulation is partly attributed to the interaction of Brd4 with RFC, conserved DNA replication machinery, which occurs through the bromodomain. Further elucidation of the role of this factor is pursued by conditional knock-out and antisense/RNAi approaches. Publications generated

本节对调节免疫系统发展的转录因子感兴趣。我们先前分离了ICSBP/IRF-8，这是一种在造血细胞中表达的DNA特异性转录因子，并表明它调节骨髓祖细胞的发育以产生巨噬细胞和颗粒细胞。我们还表明，ICSBP的引入可挽救ICSBP无效祖细胞中这些细胞的正常生长和分化。它还可以挽救树突状细胞（DC）的发育和成熟，对宿主防御很重要。 ICSBP-NULL小鼠是严重缺陷的，缺乏先天免疫力的能力，因为这些小鼠不表达IL-12P40和干扰素（Tyoe I IFNS。尽管这些细胞因子并未在ICSBP - / - / - 巨噬细胞中产生这些细胞因子，并且可以将ICSBP的重新介绍为Cytnos cdtn cdn in Murine cdtna cdn y Mirine。已开始发现ICSBP直接调节的其他靶基因。从另一个角度来看，染色质，并表征溴化群蛋白BRD4是保守BET家族的新成员，其中包含与染色质相互作用的基序。我们表明它与有丝分裂染色体相关，与染色质的强亲和力一致。最近的FRET和FLIP分析表明，BRD4和相关蛋白与活细胞中的乙酰化组蛋白相互作用。通过过表达的策略，发现BRD4可以调节细胞生长。我们表明，这种生长调节部分归因于BRD4与RFC，保守的DNA复制机制的相互作用，该复制机制通过溴化域发生。有条件的敲除和反义/RNAi方法可以进一步阐明该因素的作用。 生成的出版物