Role of Histone Acetyltransferases During Development

描述(申请人提供)：特异组蛋白乙酰转移酶(HATS)在染色质介导的多种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。研究表明，HATS既参与正常的细胞过程，也参与异常的细胞过程，导致肿瘤发生和发育障碍，这突显了HATS在生物调控中的重要性。然而，尽管有这些联系，人们对个别帽子在正常多细胞发育所需的特定组织细胞过程中扮演的特殊角色知之甚少。 本应用程序的目标是进一步定义这些角色，以及描述单个HAT所涉及的特定发展路径。果蝇是这类研究的理想模式生物，因为它具有高度特征性的发育系统，而且发现果蝇和人类共享结构和功能相关的特定HAT基因。首席研究人员已经鉴定并克隆了三种这样的果蝇帽子(Dhats)，它们与基本的人类帽子Tip60、ELP3和HBOI显示出显著的同源性。为了确定HAT的特异性和功能，特定目标1将检查每个已识别的DHAT的发育和组织类型表达模式。初步结果表明，每种DHAT在发育过程中都有不同的表达。具体目标2将进一步研究dTIP60和dELP3在发育过程中的作用。果蝇体内以GAL4为靶点的RNAi系统将被用来沉默各种不同组织和发育阶段中特定的内源性DHAT表达。识别受特定DHAT丢失影响的特定组织、细胞类型和谱系标记基因，并与特征明确的发育途径相关联，将使研究人员能够破译Tip60和ELP3在发育过程中的作用和要求。由于细胞分化途径中的许多缺陷是由HATS的错误调节引起的，因此破译单个细胞HAT功能的基础的目标可能对理解人类的生物调节和发育障碍具有深远的意义。

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.