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Ectopic Gene Expression in Thymic Epithelia that Imposes Immune Tolerance

How does the immune system distinguish friend vs. foe? The thymus gives rise to T cells that harbor specificities to virtually any pathogen; however, this stochastic process also generates specificities for self. To purge self-reactive clones from the repertoire, epithelial cells of the thymic medulla express nearly three-fourth of the coding genome to mirror the peripheral ‘self’ and display tissue-specific antigens (e.g. insulin) to prevent autoimmunity (e.g. diabetes). The Koh Lab strives to identify the determinants and developmental cues that program this somatic plasticity, allowing cells of defined epithelial lineage to activate genes that are highly restricted to other lineages. We also aim to understand how this ectopic expression is regulated to prevent disruption of carefully balanced physiological processes, e.g. blood calcium and glucose levels.

 

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Acquisition of T Cell Effector Plasticity and Leukemogenesis

T cells can elicit one of many distinct functions (e.g. kill, induce differential cytokine milieu, repress activation, tissue repair, metabolic homeostasis, etc.) and redirect their initial response to an alternate fate depending on the nature of the pathogen and environment. This T cell plasticity is central to protective immunity and its dysregulation contributes to cancer. How can T cells respond in so many different ways? How does this cellular plasticity leave it vulnerable for leukemic transformation? The Koh Lab strives to understand how the T cell-specific epigenetic circuit is established during development, and how it is broken during leukemogenesis. The intrinsic and extrinsic determinants of this process can be exploited to augment cancer immunotherapy and ameliorate leukemia progression.

 

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Chromatin: Highly Plastic Template with Memory Faculty for Specifying Cellular States

Tissues develop from specialized differentiation of cells that originate from a single zygote. Conrad Waddington described this developmental process as ‘epigenesis’. Chromatin is the template that records and transmits epigenetic information by integrating the actions of transcription factors, signaling and metabolic pathways to specify cell fate. The Koh Lab develops technology that interrogates the state and conformations of chromatin and corresponding gene network dynamics at single-cell resolution, to understand how somatic plasticity is specified during development. The organizing principles we uncover will provide insights to how chromatin states are altered in disease and avail novel therapeutic avenues.