At cell fate decision checkpoints, a precise series of events occur to establish developmentally appropriate gene expression profiles. At the molecular level, lineage-determinant transcription factors are required for the simultaneous activation and repression of genes that define the fate of a cell. Currently, it is unclear how these factors mechanistically achieve this precise control on a global level. In the immune system, naive CD4+ T helper cells begin with the potential to become a number of phenotypically distinct lineages, with key transcription factors committing them to a defined fate that is appropriate for a pathogenic insult. The T-box transcription factor T-bet is responsible for the differentiation of the Th1 cell lineage. Previous work has shown that T-bet positively regulates the effector cytokines and chemokine receptors that are the prototypic genes in Th1 cellular differentiation. To activate these select target genes, T-bet participates in at least three physically separable activities: 1) H3K27-demethylation, 2) H3K4-methylation, and 3) transactivation events that occur independent from the chromatin environment. It is currently unclear, however, whether these separable functional activities are required at all target promoters, or rather they are selectively utilized in a context-specific manner. In addition, the mechanism by which T-bet represses the gene expression profiles for the alternative helper T cell lineages and whether T-bet's ability to negatively regulate these genes requires the same or distinct activities is unknown. We will examine these questions on both a global and select target gene level. To this end, we will utilize mutant constructs deficient in each of T-bet's defined functional activities and assess their ability to regulate the global T-bet-dependent gene expression patterns in Th1 cell differentiation. We also will create mice deficient in defined interacting proteins to determine their biological relevance in regulating T-bet-dependent gene expression profiles in Type 1 immune responses. We will utilize this knowledge to model T-bet-dependent target gene networks that are based upon the mode of regulation. Together, these studies will allow us to define the mechanisms that are needed for the precise regulation of Th1 differentiation.
A new and exciting possibility in medical research is to selectively target therapeutic interventions for individual pathways that are pathogenically altered in human disease. This will allow for the greatest therapeutic benefit with the least number of unintentional detrimental side effects. In order to accomplish this goal in molecular medicine, we must precisely define the pathways that are regulated by the individual activities of the key factors involved in maintaining a healthy state. Our studies will address this from the standpoint of a key factor that regulates immune responses, which when altered, has been shown to be associated with diseases such as type 1 diabetes, ulcerative colitis, multiple sclerosis, cancer metastasis, and increased susceptibility to infectious disease.
|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|
|Oestreich, Kenneth J; Weinmann, Amy S (2012) Master regulators or lineage-specifying? Changing views on CD4+ T cell transcription factors. Nat Rev Immunol 12:799-804|
|Oestreich, Kenneth J; Weinmann, Amy S (2012) Encoding stability versus flexibility: lessons learned from examining epigenetics in T helper cell differentiation. Curr Top Microbiol Immunol 356:145-64|
|Oestreich, Kenneth J; Mohn, Sarah E; Weinmann, Amy S (2012) Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat Immunol 13:405-11|
|Oestreich, Kenneth J; Weinmann, Amy S (2012) Transcriptional mechanisms that regulate T helper 1 cell differentiation. Curr Opin Immunol 24:191-5|
Showing the most recent 10 out of 18 publications