Research focus:
- Immunobiology of T cell differentiation
- Regulation of early hematopoiesis
Work in our laboratory is focused on two major areas of interest:
- O-GlcNAc Regulation of T cell differentiation.
The focus of immunometabolism is on how metabolism controls the function of immune cells. CD4+ T cells are essential for the adaptive immune response leading to the eradication of specific pathogens. When T cells are inappropriately over-active, they can drive autoimmunity, allergic disease, and chronic inflammation.
The mechanisms by which metabolic changes influence function in CD4+ T cells are not fully understood. The post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine), dynamically cycles on and off intracellular proteins as cells respond to their environment and flux through metabolic pathway changes. As the rate of O-GlcNAc cycling fluctuates, protein function, stability, and/or localization can be affected.
We found that elevation of O-GlcNAc in T cells induces the cells to undergo aberrant differentiation, in vitro, into a pro-inflammatory cell phenotype. In addition, this pro-inflammatory phenotype, and elevated O-GlcNAcylation was observed in T cells obtained from obese mice with Type 2 diabetes. We currently are focused on identifying the intra- and extracellular metabolic factors that influence CD4+ T cell activation and differentiation and how O-GlcNAc regulates these processes.
- DOT1L regulation of embryonic hematopoiesis.
DOT1L is a histone methyltransferase that has been implicated in aggressive childhood leukemias (MLL). Our laboratory demonstrated that DOT1L is critical for erythropoiesis in the developing embryo. Loss of DOT1L in mutant mice (Dot1L-KO) results in lethal anemia during midgestation (Feng et al, 2010).
We produced a mutant mouse (Dot1L-MM) that lacks the intrinsic methyltransferase but maintains the overall structure of the DOT1L protein, to determine whether the methyltransferase activity is essential for erythropoiesis. Unlike the Dot1L-KO, Dot1L-MM embryos did not exhibit evidence of anemia. This striking difference between the Dot1L-KO and the Dot1L-MM suggests a developmental stage specific role for DOT1L in embryonic hematopoiesis. The data also suggest that a DOT1L methyltransferase-independent pathway exists during early blood development. Our current research is focused on identifying this methyltransferase-independent pathway and identifying all DOT1L targets. If DOT1L tumorigenic activity can be targeted, leaving its essential physiological roles intact, this would have high clinical implications.
