Characterization of the tetrameric monocytic leukemia zinc finger protein complex

In human cells, histones bind DNA and form chromatin, a nucleoprotein complex important for various cellular processes. Abnormal histone modification is known to play causal roles in the development of cancer. Monocytic leukemia zinc finger protein (MOZ) is a MYST-family histone acetyltransferase whose gene is rearranged in chromosomal translocations giving rise to acute myeloid leukemia. This acetyltransferase functions as a potent transcriptional coactivator of Runx1 and Runx2, two homologous transcription factors that are important for definitive haematopoiesis and osteoblast maturation, respectively. Mouse knockouts have demonstrated that MOZ is required for the maintenance of hematopoetic stem cells, and is important for erythroid and myeloid cell differentiation.Chapter I reviews the importance of chromatin regulation, MYST histone acetyltransferases and ties them together to explain how gene regulation is achieved. Chapter II addresses the characterization of the tetrameric MOZ complex, and suggests that its activity can be modulated by the presence of associated subunits such as BRPF1, and ING5. We show by histone acetyltransferase assays that MOZ and MORF activity is indeed enhanced by associated proteins. We have mapped the interaction domains of BRPF1 required for binding by MOZ, ING5, and Eaf6 in an effort to understand the mechanism of activation. Given that MOZ and ING proteins contribute to oncogenesis by chromosomal translocations and loss of function respectively, the characterization of the multisubunit complex provides novel mechanistic insights into its function in normal human cells and under conditions of leukemia or other cancers