It is well established that specific transcription factors drive the commitment of multipotent myeloid progenitors, but most of the regulatory circuits controlling these pathways remain unexplored. Understanding transcription factor function in myelopoiesis is essential for deciphering the regulation of myeloid cell differentiation. The long-term objectives of the proposed research project are to provide new information on the transcriptional mechanisms governing lineage choice and specification in myelopoiesis and ultimately, how these can be subverted to produce diseases of the monocyte/macrophage system. During myelopoiesis, specific targets of c-Myb are selectively repressed by the c-Maf transcription factor, thereby disengaging the precursor cell's Myb-driven proliferative program. Simultaneously, c-Maf mediates the activation of monocytic differentiation signals, and together these dual programs propel the commitment and differentiation of precursor cells to the myelomonocytic lineage. Thus, Maf function in myeloid cells can be viewed as both Myb-dependent and Myb-independent, and monocytic differentiation depends upon events triggered by each of these interdependent programs, a hypothesis supported by the severe multilineage hematopoietic defects found in animals that lack the c-Maf protein. We propose to dissect the molecular machinery and delineate the rules that govern Maf repression and transcription factor interaction. The goals of our research are to first clarify the cooperative mechanisms by which Myb and Maf contribute to monocytopoiesis and perhaps to the development of other hematopoietic lineages (Aim 1). An understanding of these mechanisms will be critical to defining the broader hematopoietic consequences of downstream genes affected by Maf and Myb:Maf interactions (Aim 2). Finally, because Maf is a member of a closely related multigene family with distinct expression patterns, it is possible that Maf interactions with other sequence-specific transcription factors and accessory molecules constitute a general means of transcriptional control in diverse tissues where Maf proteins are expressed, and thus may be relevant in a broader developmental context.
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