Transcription factors control gene expression by recruiting high molecular weight protein coactivator complexes to the regulatory regions of genes. Some of these complexes contain chromatin modifying enzymes. One class of such enzymes consists of histone acetyltransferases which includes the widely expressed molecules CBP, its close relative p300, and the p300/CBP-associated factor PCAF. CBP/p300 and PCAF are critical targets of viral oncoproteins which interfere with differentiation and promote cell cycle progression. In addition, the CBP and p300 genes are rearranged in chromosomal translocations associated with certain forms of leukemia. Recent evidence suggests that CBP/p300 and PCAF are regulated by signals that control cell growth and differentiation. The goal of the proposed studies is to understand the roles of CBP and PCAF during the differentiation of hematopoietic cells. Hematopoiesis serves as an ideal model system in which to study the processes of lineage commitment, cell maturation, and cell cycle exit. The hematopoietic transcription factor NF-E2 is a key regulator of erythroid and megakaryocytic gene expression. Our preliminary studies show that NF-E2 associates with and is acetylated by CBP and PCAF. Experiments in Specific Aim 1 examine the molecular and biological consequences of NF-E2 acetylation. Our preliminary results also indicate that PCAF protein levels are differentially regulated upon differentiation of distinct hematopoietic cell lineages.
Specific Aim 2 examines the role of PCAF regulation during hematopoietic cell differentiation. Furthermore, this Aim will analyze the activities and subunit compositions of the CBP and PCAF complexes during hematopoietic differentiation. Together, these studies will lead to an improved molecular understanding of acetyltransferases which stand as potential targets for pharmacological intervention in various hematological disorders.
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