Rearrangement of T Cell genome architecture regulates GVHD

Yaping Sun; Gabrielle A Dotson; Lindsey A Muir; Scott Ronquist; Katherine Oravecz-Wilson; Daniel Peltier; Keisuke Seike; Lu Li; Walter Meixner; Indika Rajapakse; Pavan Reddy

doi:10.1016/j.isci.2022.104846

Rearrangement of T Cell genome architecture regulates GVHD

iScience. 2022 Aug 6;25(9):104846. doi: 10.1016/j.isci.2022.104846. eCollection 2022 Sep 16.

Authors

Affiliations

¹ 1Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
² Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Mathematics, University of Michigan, Ann Arbor, MI, USA.

Abstract

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.

Keywords: Genetics; Genomics; Molecular biology.

Abstract

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