Role of Histone Acetyltransferases During Development

组蛋白乙酰转移酶在发育过程中的作用

• 批准号: 6820866
• 负责人: FELICE ELEFANT
• 金额: $ 7.5万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820866
• 关键词: Drosophilidae; acyltransferase; cell differentiation; enzyme activity; gene expression; genetic markers; genetic regulation; growth /development; in situ hybridization; polymerase chain reaction

DESCRIPTION (provided by applicant): Specific histone acetyltransferases (HATs) play key regulatory roles in diverse chromatin-mediated biological processes, such as gene activation, apoptosis, cell-cycle regulation, DNA replication, and repair. The importance of HATs in biological regulation is underscored by studies demonstrating their involvement in both normal cellular processes and abnormal ones, resulting in oncogenesis and developmental disorders. Despite these connections, however, little is known about the specialized roles that individual HATs play in the tissue-specific cellular processes required for proper multicellular development. The goal of this application is to further define these roles, as well as to characterize the specific developmental pathways in which individual HATs are involved. Drosophila is an ideal model organism for such studies based on its highly characterized developmental system, and the discovery that flies and humans share structurally and functionally related specific HAT genes. The principal investigator has identified and cloned three such Drosophila HATs (dHATs) that show significant homology to essential human HATs TIP60, ELP3, and HBOI. To define HAT specificity and function, Specific Aim 1 will examine the developmental and tissue-type expression patterns of each identified dHAT. Preliminary results indicate that each dHAT is differentially expressed during development. Specific Aim 2 will further investigate the roles of dTIP60 and dELP3 during development. A GAL4 targeted RNAi based system in Drosophila will be used to silence specific endogenous dHAT expression in a variety of distinct tissues and developmental stages of choice. Identifying specific tissues, cell types, and lineage marker genes affected by particular dHAT loss and making associations with well-characterized developmental pathways will allow the investigator to decipher the roles and requirement for TIP60 and ELP3 during development. As many defects in cell differentiation pathways are caused by misregulation of HATs, the goal of deciphering the basis of individual cellular HAT function will likely have far reaching implications for the understanding of human biological regulation and developmental disorders.

描述（由申请人提供）：特异性组蛋白乙酰转移酶（HAT）在多种染色质介导的生物过程中发挥关键调节作用，如基因激活、细胞凋亡、细胞周期调节、DNA复制和修复。 HAT在生物调节中的重要性被研究所强调，这些研究表明它们参与正常细胞过程和异常细胞过程，导致肿瘤发生和发育障碍。 然而，尽管有这些联系，人们对单个HAT在适当的多细胞发育所需的组织特异性细胞过程中发挥的特殊作用知之甚少。 本申请的目的是进一步定义这些角色，以及表征个体HAT参与的特定发育途径。 果蝇是一个理想的模式生物，基于其高度特征化的发育系统，以及发现苍蝇和人类共享结构和功能相关的特定HAT基因。 主要研究者已经鉴定并克隆了三种这样的果蝇HAT（dHAT），它们与人类必需的HAT TIP60、ELP3和HBOI具有显著的同源性。 为了定义HAT特异性和功能，具体目标1将检查每个鉴定的dHAT的发育和组织类型表达模式。 初步结果表明，每个dHAT在发育过程中差异表达。 具体目标2将进一步研究dTIP60和dELP3在发育过程中的作用。 果蝇中基于GAL4靶向RNAi的系统将用于沉默多种不同组织和所选发育阶段中的特异性内源性dHAT表达。 鉴定受特定dHAT损失影响的特定组织、细胞类型和谱系标志物基因，并与充分表征的发育途径相关联，将使研究者能够解读发育期间TIP60和ELP3的作用和要求。 由于细胞分化途径中的许多缺陷是由HAT的误调节引起的，因此破译单个细胞HAT功能的基础的目标可能对理解人类生物调节和发育障碍具有深远的影响。