Multi-omic analysis reveals dynamic changes of three-dimensional chromatin architecture during T cell differentiation (Hi-C)

Background: Activation of T cells results in widespread changes in transcriptional programs and multi-level remodeling of three-dimensional genome architecture. Although many efforts have been made in dissecting the epigenomic regulation during T cell activation and differentiation, it remains to be investigated in depth how alterations in the local and global chromatin structure coordinate gene expression in this process. Results: We characterize dynamic changes at different levels of chromatin organization during Naive CD4+ T (Naive) differentiation into T helper 17 (Th17) and T helper 1 (Th1) cells using Hi-C, RNA-Seq and ATAC-Seq assays. As a result of T cell activation, extensive changes occur at the transcriptome, chromatin accessibility and higher-order structure levels. We observe decreased short-range chromatin interactions and increased extra-long-range chromatin interactions upon activation. At compartment level, although A/B compartments have no apparent global switch, the intensity of compartmentalization markedly alters in activated T cells. At TAD level, a fraction of TADs is rearranged with increase TAD number upon activation. In addition, we identify promoter-enhancer (P-E) loops, many of which are associated with T cell activation or cell-type specificity, including Rorc encoding ROR?t (retinoic-acid-receptor-related orphan receptor gamma t) that facilitates Th17 differentiation and Hif1a (hypoxia-inducible factor 1a) that responds to intracellular oxygen levels in Th1. Conclusion: T cell activation is conserved at multiple levels across T helper cells and species. From the 3D genome perspective, these results provide fresh insights into heterogeneity and plasticity of T helper cells during T cell activation based on chromatin reorganization. Overall design: Cells were isolated from mouse pooled lymph nodes and spleens by magnetic nanoparticle based on isolation kit for naive CD4+ T cells from Miltenyi Biotec.