Browsing by Author "Muir, Lindsey A."

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    Rearrangement of T Cell genome architecture regulates GVHD
    (Elsevier, 2022-08-06) Sun, Yaping; Dotson, Gabrielle A.; Muir, Lindsey A.; Ronquist, Scott; Oravecz-Wilson, Katherine; Peltier, Daniel; Seike, Keisuke; Li, Lu; Meixner, Walter; Rajapakse, Indika; Reddy, Pavan; Pediatrics, School of Medicine
    WAPL, cohesin's DNA release factor, regulates three-dimensional (3D) chromatin architecture. The 3D chromatin structure and its relevance to mature T cell functions is not well understood. We show that in vivo lymphopenic expansion, and alloantigen-driven proliferation, alters the 3D structure and function of the genome in mature T cells. Conditional deletion of WAPL, cohesin's DNA release factor, in T cells reduced long-range genomic interactions and altered chromatin A/B compartments and interactions within topologically associating domains (TADs) of the chromatin in T cells at baseline. WAPL deficiency in T cells reduced loop extensions, changed expression of cell cycling genes and reduced proliferation following in vitro and in vivo stimulation, and reduced severity of graft-versus-host disease (GVHD) following experimental allogeneic hematopoietic stem cell transplantation. These data collectively characterize 3D genomic architecture of T cells in vivo and demonstrate biological and clinical implications for its disruption by cohesin release factor WAPL.