Understanding MORF-mediated hematological gene regulatory mechanisms

Project Summary The monocytic leukemia zinc-finger protein-related factor MORF is a transcriptional coactivator and a catalytic subunit of the histone acetyltransferase MORF (named after its catalytic subunit) complex. MORF regulates expression of hematologic, cardiac and developmental genes and plays a pivotal role in the development of the hematopoietic system and the formation of blood cells. Aberrant acetyltransferase activity of MORF is linked to aggressive forms of leukemia, blood diseases and cardiovascular abnormalities. The MORF driven epigenetic mechanisms in the normal and disease states remain poorly understood, and characterization of these mechanisms may pave the way for the development of novel strategies to diagnose, prevent or treat these diseases. Our preliminary data indicate a multivalent engagement of MORF with chromatin through its histone and DNA binding domains that regulate enzymatic activity and genomic localization of the complex. The molecular basis underlying novel functions of MORF and biological consequences are unknown and will be determined in the proposed studies. The results generated in this work will offer a comprehensive understanding of the molecular mechanisms by which the MORF subunit is bound to specific genomic sites and its enzymatic activity is regulated, provide atomic-resolution insight into MORF signaling pathways that may constitute new targets for therapeutic interventions, aid in our understanding of the etiology of hematological and cardiovascular diseases associated with aberrant MORF activity, and enhance our knowledge of the fundamental principles underlying the ‘epigenetic code’ writing and recognition.