The importance of properly establishing and maintaining epigenetic states in cellular development is unmistakable. The critical role for this process is highlighted by the number of mutations in epigenetic modifying proteins that are associated with human diseases, with a particularly high prevalence found in cancers. Similarly in the immune system, the precise coordination of epigenetic events is also required for cellular differentiation, and blood cancers such as leukemia and lymphoma often have mutations that impact the functions of epigenetic-modifying complexes. Recent research efforts have focused on profiling epigenetic modifications to define their cell-type and activation-state specific distribution. There also has been an emphasis on correlating changes in epigenetic patterns with human disease states. However, a major gap in our current knowledge has been defining the events that control the site specific targeting of the enzymatic machinery that regulates epigenetic patterns in unique cellular states. This is a high impact area of research because cell-type and activation-state specific epigenetic patterns cannot be explained without knowledge of the mechanisms that direct epigenetic-modifying complexes to unique sites in different cellular contexts. The focus of this proposal will be on the site-specific genomic targeting and functional activity of the DNA- demethylase Tet1 in helper T cells. Until recently, i was unclear if a cell possessed enzymatic machinery with the potential to actively remove the methyl modification on cytosine bases within the DNA. Some of the first hints that active DNA demethylation occurs in mammalian cells came from studies in T cells examining the IL-2 promoter, where the DNA replication-independent removal of cytosine methylation modifications was experimentally observed. The discovery of the ten-eleven-translocation (TET) protein family provided the first evidence that cytosine methylation could be broken down by a cellular enzyme into a hydroxymethylated state, with the potential to then be successively converted to the unmethylated state. Notably, mutations in TET proteins are found in a number of blood cancers, highlighting the importance of this protein family in immune cell development. In this proposal, we will for the first time define the mechanisms that target Tet1 to specific genomic loci in helpe T cells and its importance in the immune response. These studies will form the basis for understanding the site-specific targeting of Tet1 to loci in helper T cell development and how this impacts cellular transitions as well as the functional potential of the cells during an immune response to viral infection.
Epigenetic modifications, such as DNA and histone methylation, provide additional layers of information about the genome to promote cell type and activation specific gene programs. Aberrant epigenetic states, as well as mutations in epigenetic modifying enzymes, are associated with human diseases including a high prevalence in blood cancers. Our studies will define the functional role for the DNA demethylase Tet1 in immune cells.
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