Description

Stimulus-mediated chromatin reorganization for T-helper cell differentiation

Han-Yu Shih¹, Ping Wang², Zhonghui Tang², Hong-Wei Sun¹, Stephen R. Brooks¹, Fred P. Davis¹, Yuka Kanno¹, Yijun Ruan², John O’Shea¹

¹National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA; ²The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA

Naïve CD4⁺ T-cells differentiate into a variety of lineages depending on the spectrum of stimuli.This lineage-specifying process is critical for selecting proper host defending programs against pathogens and is tightly regulated by epigenetic reprogramming.Although the lineage-specific chromatin structures have been characterized on T-cell lineage signature gene loci, the full scope of chromatin reorganization during T-cell differentiation remains unclear. To genome-wide characterize the dynamics of chromatin architecture during T-cell differentiation, we applied an Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) naïve CD4⁺ T-cells and differentiated T-helper 1 (Th1) and Th2 cells. By incorporating with Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET), we revealed dynamic T-cell lineage-specific regulomes that involve complex enhancer-promoter interactions. To dissect the chromatin alterations that are mediated by distinct signaling pathways, we analyzed transcription factor motifs among stimulus-specific regulatory elements and identified putative regulatory networks for lineage specification. We further evaluated chromatin accessibility at different time points during in vitro Th differentiation and documented dynamic chromatin accessibility upon distinct stimuli. Our study provides a comprehensive understanding of the nature of chromatin landscapes for T-cell lineage specification.