The Role of Early Growth Response Transcription Factors in Hematopoietic DevelopmentPublic Deposited
The orderly process of hematopoietic differentiation is governed in large part by the coordinated transcription of specific genes. Deregulation of normal differentiation processes can lead to disease states including immunodeficiency, autoimmune disease, and leukemia. This research focuses on the family of transcription factors known as the early growth response (Egr) family consisting of Egr1, Egr2, Egr3, and Egr4. These proteins share a highly homologous DNA-binding domain and are rapidly induced by a variety of stimuli, including growth factors, cytokines, and T- and B-cell receptor engagement. Numerous recent studies have implicated Egr1, Egr2, and Egr3 genes in the differentiation of both the myeloid and lymphoid lineages. In myeloid cells, Egr genes are thought to participate in the process of lineage commitment and maturation of monocytic cells. Likewise in T cells, multiple Egr genes are induced during development. In both cases however, the requirement for Egr function and the mechanism by which Egr genes promote proper differentiation are not fully understood. Loss of function experiments are often hindered by the fact that multiple Egr proteins are often coordinately expressed in the same cell, allowing related family members to compensate for the loss of a single Egr protein. In the first section of this thesis, we investigated the role of Egr proteins in monocyte/macrophage differentiation using both mice deficient in multiple Egr family members and dominant negative constructs capable of inhibiting all Egr proteins. Surprisingly, we found that Egr function is neither required for, nor specific to, monocyte/macrophage differentiation, challenging long-standing assumptions. In the second section, we investigated whether Egr1 and Egr3 may play redundant roles in early thymocyte differentiation. Using mice doubly deficient for both Egr1 and Egr3, we discovered a novel, cell autonomous increase in apoptosis and concomitant differentiation block which was not seen in mice lacking only one Egr gene. Global transcriptional analysis revealed that Egr1 and Egr3 are required for the proper expression of a large number of metabolic genes, providing new insights into the mechanism by which Egr proteins promote normal T cell development.