Role of Histone Acetyltransferases During Development

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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.