Hematopoiesis is a complex, highly coordinated process in which proper function of cell-lineage and stage-specific gene regulation required in order to instruct stem cells to undergo self-renewal or adopt specific cell fates, and dysregulation of this process results in development of diseases such as Acute Myeloid Leukemia (AML). Transcription factors such as CCAAT Enhancer Binding Protein ? (C/EBPa) have been identified by our laboratory and others as playing a critical role in this process. Recently, a number of reports have Implicated epigenetic modifications, including histone acetylation, in normal hematopoiesis and leukemogenels. In this project, we will study the role of lysine acetyltransferases (KATs) In these processes, both with respect to their effects on C/EBPa, as well as on other targets. Including histones. These studies will lead to new understanding of how tissue-specific and lineage-specific gene expression is controlled through acetylation. Furthermore, since KATs work through an enzymatic activity, such studies may lead to development of new therapeutic approaches in AML. Therefore, the Specific Aims are:
Aim 1 : To investigate the role of acetylation of C/EBPa in granulopoiesis: In this aim, we will investigate how the transcription factor C/EBPa can be negatively or positively affected by GCN5 and TIP60 signaling pathways, respectively, at the post-translational level. We will specifically identify the site(s) acetylated by GCN5 and TIP60, and determine if C/EBPa acetylation is a stage or lineage(s) specific phenomenon. Our initial study suggests that GCN5 might represent a potential drug target for restoring C/EBPa function.
Aim 2 : To understand the role of two key epigenetic enzymes, the lysine acetyltransferases GCN5 and TIP60, in hematopoiesis and leukemia: Our studies will bridge between vast existing biochemical data on GCN5 and TIP60 acetylases and chromatin remodeling activities to their in-vivo functions in hematopoiesis. Furthermore, our studies will answer the question whether GCN5 or TIP60 are indispensable for hematopoietic stem cell (HSC) function. This project will interact with most of the other projects in this program, including investigating the interactions of acetyltransferases and their inhibition on BHS profiles (Project 1) and inhibitors of chromodomain proteins (Project 4). In addition, the project will utilize Core B for leukemic samples used in the project, as well as depend on biostatistic support (Core C). The ultimate aim is to develop new therapies based on these studies.
Expected outcome: Our studies have the potential to uncover novel reversible C/EBPa protein modifications that could be directly relevant to leukemogenesis, and therefore help develop targeted therapies. Our studies on loss of function of GCN5 and TIP60 will underscore the role of these acetyltransferases in hematopoiesis and leukemia.
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