4.7 Article

Rearrangement of T Cell genome architecture regulates GVHD

Journal

ISCIENCE
Volume 25, Issue 9, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.isci.2022.104846

Keywords

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Funding

  1. University of Michigan Genome Science Training Program (GSTP) Fellowship - NHGRI [P01HL149633, R01CA217156, 5T32HG000040-27]
  2. University of Michigan Genome Science Training Program (GSTP) Fellowship - NHGRI [R01HL 152605]

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This study reveals that WAPL deficiency affects the 3D structure and function of the genome in mature T cells, with implications for their biological and clinical characteristics.
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 topically 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.

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