The Poholek Lab

Tissue specific functions of Blimp-1

Transcription factors play a critical role in modulating the transcriptome and epigenome of cells. Blimp-1 is a BTB/POZ zinc finger transcription factor expressed by many cell types, including T and B cells. In T cells, we have identified context-dependent functions of Blimp-1 controlling T cell differentiation and effector function and are exploring the molecular regulation and function of Blimp-1 as a model transcription factor that controls immune cells in health in disease. Our research on Blimp-1 seeks to answer the following questions:

1. How is Blimp-1 regulated in a cell-type specific manner?

2. What is the molecular function of Blimp-1 in vivo in various immunological contexts?

Our studies have uncovered novel genomic elements controlling the expression of Blimp-1 and the tissue-specific functions of Blimp-1 that control autoimmunity while also promoting responses to allergens. Using genetic mouse models and NextGen sequencing technologies, we are, at the molecular level, exploring how this important transcription factor shapes T cell differentiation and function at homeostasis and in the face of contextual environmental changes.

Epigenetic landscape of T cell exhaustion in the tumor

In collaboration with Greg Delgoffe, PhD, at the UPMC Hillman Cancer Center, we are exploring the epigenetics of T cells in murine tumors using a new low-cell number ChIP-seq assay (CUT & RUN) developed by Steven Henikoff, PhD, at the Fred Hutchinson Cancer Research Center. As T cells enter a tumor’s micro-environment, they experience a unique combination of signals that promote a state of T cell dysfunction (also called exhaustion). Our lab is working to understand the transcriptomic and epigenomic landscape of T cell exhaustion in a tumor in order to understand the signals that drive exhaustion and identify novel therapeutic targets for immunotherapy.

Intersection of Metabolism and Epigenetics

T cells are unique in that they can rapidly shift their metabolism after activation as well as undergo rapid cell division. The cellular mechanics that underlie these changes are unique to T cells and are in the early stages of being understood. Our lab is using NextGen sequencing technologies to modulate the environmental signals and metabolic requirements that T cells experience after activation to determine the intersection of these inputs on the epigenetic landscape. Our goal is to understand how shifts in metabolites or environmental signals impact T cell differentiation and function from the initiation of T cell activation at the chromatin level so as to understand the plasticity and heterogeneity that exists in the T cell compartment in vivo.