SUMMARY
Fotini Gounari, Ph.D., researches molecular processes of physiologic immune cell development and molecular mechanism of T cell and T-regulatory cell (Treg) plasticity. Studies include the deregulation of immunity in pathologies, including autoimmunity and cancer.
Dr. Gounari's lab focuses on elucidating epigenetic and transcription regulatory networks that control T cell development and shape a healthy and balanced T cell immunity. T cell maturation involves coordinated changes in the chromatin landscape that enable expression of stage-specific transcription programs. Numerous regulators are essential for T cell development. How these regulators harmonize their actions is poorly understood. A major focus of the lab is understanding the role of the critical T cell-specific DNA-binding protein Tcf-1. Dr. Gounari and her team are exploring its role, along with other regulators, in orchestrating the epigenetic and transcriptional transitions in developing T cells and Tregs.
Tcf-1 is a T cell-specific member of the Tcf/Lef family of DNA-binding proteins. As such, it can respond to the multifunctional protein β-catenin in the context of the canonical Wnt signaling. Uncontrolled activation of β-catenin in T cells has pathologic consequences as seen in human disease. In thymocytes, it predisposes thymocytes to Tcf-1-dependent genomic instability leading to T cell transformation and thymic lymphomas. These lymphomas have chromosomal translocations like those found in human T cell acute lymphoblastic leukemia (T-ALL). Current studies investigate how β-catenin directs Tcf-1 to promote genomic instability and T cell transformation. In inflammatory bowel disease (IBD) and colorectal cancer, T cells and particularly Tregs express elevated levels of β-catenin. This imprints disease-promoting, proinflammatory properties on T cells and Tregs. Dr. Gounari's lab focuses on defining how the deregulated activation of β-catenin and its partnership with Tcf-1 changes the physiological functions of Tregs to promote disease pathologies and tumor progression.
Focus areas
- Molecular functions and interactions of Tcf-1 in developing thymocytes. The lab's studies address the hypothesis that Tcf-1 participates in distinct regulatory protein complexes and cooperates with other regulators (Lef-1, HEB, Runx1 and Ikaros) to dynamically modulate chromatin conformation and expression profiles that guide thymocyte development. Determining how these regulators coordinate to establish epigenetic and chromatin conformation states will provide a novel and comprehensive molecular model of how the programs of developing thymocytes are modulated.
- Regulation of Treg plasticity and proinflammatory conversion in IBD and colon cancer. The plasticity and functional diversity of Tregs are essential for the maintenance of healthy immunity, but are exploited in disease. Findings in Dr. Gounari's lab indicate that β-catenin, Tcf-1 and HEB partner with Foxp3 to regulate the diverse Treg suppressive functions, which can be selectively modulated during chronic inflammation. Current studies address the hypothesis that β-catenin controls the access of Foxp3 and HEB to select Tcf-1-bound chromatin sites to differentially regulate Treg suppressive functions and diversity.
- Mechanisms that promote genomic instability and T cell transformation. Understanding the mechanisms promoting chromosomal translocations of the rearranging receptor loci in leukemia and lymphoma remains incomplete. Dr. Gounari and her team recently found that aberrantly activated β-catenin redirects Tcf-1 binding to novel DNA sites to alter chromatin accessibility and downregulate genome-stability pathways. Impaired homologous recombination DNA repair and replication checkpoints lead to retention of DNA double-strand break (DSBs) that promote translocations and transformation of double positive (DP) thymocytes. The resulting lymphomas, which resemble human T-ALL, are sensitive to PARP inhibitors (PARPi). Current studies investigate whether PARPi could offer therapeutic options in hematologic malignancies with active Wnt/β-catenin signaling.
Significance to patient care
Understanding the molecular basis of physiological T cell development, and deregulation of these processes in disease, provides knowledge for targeted treatment of diseases.
Professional highlights
- Study section, Leukemia Research Foundation, 2008-2022.
- Permanent member, Cellular and Molecular Immunology B Study Section, National Institutes of Health, 2015-2019.
- Liaison to academia, executive council, Autumn Immunology Conference, 2011-2016.
- Chair, sponsor liaison committee, Thymus 2012 International Conference, 2012.