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

Multi-omic analysis of differentiating naive T cells highlights dynamic changes in three-dimensional chromatin architecture that occur during T helper cell differentiation. Cell differentiation results in widespread changes in transcriptional programs as well as multi-level remodeling of three-dimensional genome architecture. Nonetheless, few synthetically investigate the chromatin higher-order landscapes in different T helper (Th) cells. Using RNA-Seq, ATAC-Seq and Hi-C assays, we characterize dynamic changes in chromatin organization at different levels during Naive CD4(+) T cells differentiation into T helper 17 (Th17) and T helper 1 (Th1) cells. Upon differentiation, we observe decreased short-range and increased extra-long-range chromatin interactions. Although there is no apparent global switch in the A/B compartments, Th cells display the weaker compartmentalization. A portion of topologically associated domains are rearranged. Furthermore, we identify cell-type specific enhancer-promoter loops, many of which are associated with functional genes in Th cells, such as Rorc facilitating Th17 differentiation and Hif1a responding to intracellular oxygen levels in Th1. Taken together, these results uncover the general patterns of chromatin reorganization and epigenetic landscapes of gene regulation during T helper cell differentiation.

Automated summary

Multi-omic analysis reveals dynamic changes in three-dimensional chromatin architecture during T helper cell differentiation. The differentiation process leads to widespread changes in transcriptional programs and remodeling of three-dimensional genome architecture. Using multiple assays, we identify alterations in chromatin organization and topologically associated domains during CD4(+) T cell differentiation into Th17 and Th1 cells. We also identify cell-type specific enhancer-promoter loops associated with functional genes in Th cells. Overall, these results provide insights into the epigenetic regulation of T helper cell differentiation.