Three-dimensional genome structure and chromatin accessibility reorganization during in vivo induction of human T cell tolerance

Abstract

SUMMARYAchieving T cell tolerance is a pivotal goal for the field of transplantation and autoimmune diseases. Here, we characterized the gene expression profiles, 3D genome architecture and chromatin accessibility in human steady-state and tolerant T cells, which had been induced in healthy donors by granulocyte-colony-stimulating factor in vivo. We provided the first high-resolution 3D genomic landscape of human tolerant T cells in vivo and identified highly expressed suppressor of cytokine signaling 1 (SOCS1), which is essential for maintaining T cell tolerance and was validated by ex vivo experiments. Mechanistically, SOCS1 is activated by STAT3, which mediates a new interaction between the SOCS1 locus and downstream super-enhancers and is accompanied by the disruption of the CTCF loop between the SOCS1 locus and upstream heterochromatin. This competitive regulation pattern between STAT3 and CTCF is present in the whole genome. Our study defines a regulatory model of transcription factors and provides insight into the induction of immune tolerance.