The coordination of cellular function to developmental and environmental cues is essential for organismal growth and adaptation. Cells have a remarkable ability to sense diverse stimuli and make regulatory decisions to elicit an appropriate response. Our laboratory is interested in the molecular underpinnings of this cellular decision-making. Seminal ?receptor-switch? experiments demonstrated that the cell?s sensing apparatus does not alone promote a specific cell fate. Rather, the cell?s sensing mechanism triggers a pre-existing nuclear program that was poised during development. How is this pre-existing program established? At what stage in development does it occur? What are the determinants that establish and maintain this potential for lineage- specific effector responses? The long-term goal of the laboratory is to define the biological processes that provide answers to these fundamental questions. Our model system is T cells, an ideal framework because the stages of development are highly characterized and the cells are widely available. Our approach focuses on the regulation of chromatin, i.e. the 6 billion bases of human DNA wrapped around nucleosomes that can take on different conformations to define gene activity and cellular identity. One of the modes by which chromatin is regulated is through the actions of chromatin remodeling complexes that use energy from ATP to modify which regions of the genome are accessible to transcription factors and signaling pathways. We have recently identified a novel chromatin remodeling complex that promotes the accessibility of genes encoding specialized T cell function. This ATPase motor acts early in development to poise cells even prior to the expression of the T cell receptor. In the next 5 years, we aim to identify the subunit composition of this novel chromatin remodeling complex and the direct mechanistic modes that mediate complex targeting and function at T cell effector loci. Achievement of our research goals will also provide a foundation for advances in clinical applications of T cell biology, e.g modulation of T cell effector programming to enhance the efficacy of vaccination, cancer immunotherapy, or tolerance induction for autoimmunity.
The long-term goal of the proposed research is to understand how cells acquire the capacity to elicit specific responses to environmental cues. We aim to define the mechanistic roles of a novel chromatin remodeling complex in equipping T cells early in development with the potential to kill, secrete cytokines, and promote other T cell-specific functions. Understanding these fundamental processes will allow the modulation of T cell effector programming which can enhance vaccination, cancer immunotherapy and ameliorate autoimmunity.
