RT Journal Article
SR Electronic
T1 Rearrangement of T Cell Genome Architecture Regulates GVHD
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.23.427857
DO 10.1101/2021.01.23.427857
A1 Yaping Sun
A1 Gabrielle A. Dotson
A1 Lindsey A. Muir
A1 Scott Ronquist
A1 Katherine Oravecz-Wilson
A1 Daniel Peltier
A1 Keisuke Seike
A1 Lu Li
A1 Walter Meixner
A1 Indika Rajapakse
A1 Pavan Reddy
YR 2022
UL http://biorxiv.org/content/early/2022/05/11/2021.01.23.427857.abstract
AB The cohesin complex modulates gene expression and cellular functions by shaping three-dimensional (3D) organization of chromatin. WAPL, cohesin’s DNA release factor, regulates 3D chromatin architecture. The 3D genome structure and its relevance to mature T cell functions in vivo is not well understood. We show that in vivo lymphopenic expansion, and allo-antigen driven proliferation, alters the 3D structure and function of the genome in mature T cells. Conditional deletion of Wapl in T cells reduced long-range genomic interactions, altered chromatin A/B compartments and interactions within topologically associating domains (TADs) of the chromatin in T cells at baseline. Comparison of chromatin structure in normal and WAPL-deficient T cells after lymphopenic and allo-antigen driven stimulation revealed reduced loop extensions with changes in cell cycling genes. WAPL-mediated changes in 3D architecture of chromatin regulated activation, cycling and proliferation of T cells in vitro and in vivo. Finally, WAPL-deficient T cells demonstrated 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.Competing Interest StatementThe authors have declared no competing interest.