Chip-Seq analysis on developing gamma-delta T cells

ABSTRACT: gd T cells are increasingly understood to play critical roles in host defense and can also contribute to immune mediated pathology; however, their origins remain poorly understood. There is growing evidence suggesting that immature bipotent progenitors in the thymus are instructed to adopt the ab and γδ fates, respectively, by differences in T cell receptor (TCR) signal strength or duration, with stronger and more prolonged signals directing adoption of the gd fate. These differences in TCR signaling instruct fate through graded induction of Id3, which in turn, produces graded reductions in the ability of E box DNA binding proteins (E proteins) to bind DNA. While E proteins play a central role in regulating lymphoid fate decisions, their downstream gene targets through which they specify fate have not been identified. Understanding how E proteins control gd lineage commitment requires a comprehensive, network-based approach. Consequently, we employed ChIP-Seq to identify the enhancers whose occupancy by E-proteins was altered by TCR signaling during gd lineage commitment and we identified their targets using a chromosome capture method termed Hi-C. These data were then integrated into a comprehensive, E-protein-focused, genome-wide network describing the genomic reorganization that occurs during gd lineage commitment. These studies revealed that E protein occupancy of enhancers was far more dramatically remodeled in progenitors adopting the gd lineage fate than in uncommitted progenitors exposed to the same selecting environment and has led to the identification of specific regulatory elements through which gd lineage commitment and effector function is controlled. One such element plays a critical role in controlling the expression of the transcription factor (TF) ThPOK, as well as the effector function of γδ T cells. Thus, our comprehensive approach has provided critical new insights into the molecular processes orchestrating gd lineage commitment and provides a framework for molecular dissection of both lineage commitment and effector function.

ORGANISM(S): Mus musculus

PROVIDER: GSE162290 | GEO | 2021/03/10

REPOSITORIES: GEO