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
1Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
iScience. 2022 Aug 6;25(9):104846. doi: 10.1016/j.isci.2022.104846. eCollection 2022 Sep 16.
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 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 and 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 and demonstrate biological and clinical implications for its disruption by cohesin release factor WAPL.
黏连蛋白的DNA释放因子WAPL调节三维（3D）染色质结构。3D染色质结构及其与成熟T细胞功能的相关性尚未完全明确。我们发现，淋巴细胞减少引起的扩增以及同种异体抗原驱动的增殖会改变成熟T细胞中基因组的3D结构和功能。在T细胞中条件性缺失黏连蛋白的DNA释放因子WAPL，会减少长程基因组相互作用，并改变T细胞染色质的A/B区室以及拓扑相关结构域（TAD）内的相互作用。T细胞中WAPL缺陷会减少环延伸，改变细胞周期基因的表达，并降低抗原刺激后的增殖，以及减轻实验性异基因造血干细胞移植后的移植物抗宿主病（GVHD）的严重程度。这些数据共同描绘了T细胞的3D基因组结构，并证明了黏连蛋白释放因子WAPL对其破坏所产生的生物学和临床意义。
