Cancer Genetics, Immunology
Area of interest
Our research aims to dissect the epigenetic and transcriptional mechanisms that shape T cell lineage specification during development in the thymus as well as in the periphery upon antigen (microbial, viral) encounter. We are studying epigenetic regulators that fine tune gene expression and control transcriptional networks. Moreover, we investigate how specific transcription factors drive gene expression and define T cell lineage fate. We are particularly interested in the Ten Eleven Translocation (TET) family of proteins that consists of 3 members; TET1, TET2 and TET3. TET proteins are instrumental in the process of DNA demethylation. Via their catalytic function can oxidize 5 methylcytosine (5mC) to 5 hydroxymethylcytosine (5hmC). Aberrant DNA methylation has been reported in various cancers. Importantly, Tet2 is one of the most frequently mutated genes in hematological malignancies. Also, mutations in Tet1 and Tet3 have been reported in patients but are less frequent compared to Tet2. Moreover, studies using various mouse models have demonstrated that TET proteins can act as tumor suppressors.
We are using genetically modified mice to interrogate the function of TET proteins specifically in T cells. Aberrant expression of TET proteins can impact T cell differentiation and function and ultimately result in inflammation, autoimmunity or malignant transformation (T cell leukemias and lymphomas). To answer our questions we are using gene deficient mouse models, primary cell culture, multiparameter Flow Cytometry, molecular biology assays and next generation sequencing technologies to elucidate the regulatory information in cells of interest (transcriptome, epigenome, transcription factor occupancy). Understanding the differences between physiological versus pathological T cell differentiation and immune response is fundamental in order to manipulate T cells to design better, more efficient therapies while minimizing side effects. Thus, our research is highly translational and our ultimate goal is to combat human disease.