Lineage-restricted transcription factors play a critical role in the hematopoietic differentiation process and the deregulation of even a single factor can lead to disease states such as leukemia, autoimmunity, and allergic reactions. Part of how this occurs is that the selective loss of a factor can drastically alter the development of critical effector cell populations. Therefore, identifying the gene expression cascades influenced by these factors will allow us to address the molecular mechanisms that contribute to the disease phenotypes. The transcription factor T-bet appears to play a significant role in the development of CD4+ T helper 1 cells. Th1 cells secrete IFNgamma and are important in the development of cell-mediated immunity. A hyperactive Th1 response can contribute to autoimmune diseases such as Crohn's disease and type 1diabetes. In addition to Th1 cells, T-bet is also expressed in multiple lineages in the immune system and is thought to contribute to cell-specific functions in each effector cell population. In the absence of T-bet, cell-specific defects occur in natural killer, dendritic, and B cells. It is also worth noting that murine disease models for Crohn's disease, asthma, and lupus have all been established by altering T-bet levels. Therefore, one may hypothesize that T-bet plays an important role in the developing immune response. The main goal of this proposal is to address the molecular mechanisms behind T-bet's role in the individual hematopoietic effector cell populations.
Aim 1 is designed to identify direct T-bet target genes in each cell population. Is T-bet targeted to loci in a cell-specific manner or does it interact with the same genes in all cellular settings? To address this question, target gene identification strategies will be employed that utilize modifications to the chromatin immunoprecipitation procedure. These techniques will only identify genes that are directly bound by T-bet within the context of a given nuclear environment.
In Aim 2, the functional consequence of T-bet's association with select promoters will be examined to determine if this interaction is productive in the different cellular settings. The studies in Aim 1 and 2 will provide a means to address T-bet's cell-specifications.
Aims 3 and 4 will address the role T-bet plays in the transcriptional regulation of a few select target genes. Does T-bet function as a transcriptional activator or repressor? Does T-bet influence chromatin events or aid in RNA polymerase II recruitment to the promoter? Detailed transcriptional regulation studies of a few select target genes will aid in answering these questions.
|Chisolm, Danielle A; Weinmann, Amy S (2018) Metabolites, genome organization, and cellular differentiation gene programs. Curr Opin Immunol 51:62-67|
|Chisolm, Danielle A; Savic, Daniel; Moore, Amanda J et al. (2017) CCCTC-Binding Factor Translates Interleukin 2- and ?-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs. Immunity 47:251-267.e7|
|Gibson, Sara A; Yang, Wei; Yan, Zhaoqi et al. (2017) Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation. J Immunol 198:4244-4254|
|Botta, Davide; Fuller, Michael J; Marquez-Lago, Tatiana T et al. (2017) Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol 18:1249-1260|
|Hough, Kenneth P; Chisolm, Danielle A; Weinmann, Amy S (2015) Transcriptional regulation of T cell metabolism. Mol Immunol 68:520-6|
|Weinmann, Amy S (2014) Regulatory mechanisms that control T-follicular helper and T-helper 1 cell flexibility. Immunol Cell Biol 92:34-9|
|Oestreich, Kenneth J; Read, Kaitlin A; Gilbertson, Sarah E et al. (2014) Bcl-6 directly represses the gene program of the glycolysis pathway. Nat Immunol 15:957-64|
|Weinmann, Amy S (2014) Roles for helper T cell lineage-specifying transcription factors in cellular specialization. Adv Immunol 124:171-206|
|Buckingham, Kati J; McMillin, Margaret J; Brassil, Margaret M et al. (2013) Multiple mutant T alleles cause haploinsufficiency of Brachyury and short tails in Manx cats. Mamm Genome 24:400-8|
|Oestreich, Kenneth J; Weinmann, Amy S (2012) T-bet employs diverse regulatory mechanisms to repress transcription. Trends Immunol 33:78-83|
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