Title: Distinct and temporary-restricted epigenetic mechanisms regulate human αβ and γδ T cell development
Author: Juliette Roels, Anna Kuchmiy, Matthias De Decker, Steven Strubbe, Marieke Lavaert, Kai Ling Liang, Georges Leclercq, Bart Vandekerckhove, Filip Van Nieuwerburgh, Pieter Van Vlierberghe, Tom Taghon
Abstract: The development of TCRαβ and TCRγδ T cells comprises a step-wise process in which regulatory events control differentiation and lineage outcome. To clarify these mechanisms, we employed RNA-sequencing, ATAC–sequencing and ChIPmentation on well-defined thymocyte subsets that represent the continuum of human T cell development. The chromatin accessibility dynamics show clear stage specificity and reveal that human T cell-lineage commitment is marked by GATA3- and BCL11B-dependent closing of PU.1 sites. A temporary increase in H3K27me3 without open chromatin modifications is unique for β-selection, whereas emerging γδ T cells, which originate from common precursors of β-selected cells, show large chromatin accessibility changes due to strong T cell receptor (TCR) signaling. Furthermore, we unravel distinct chromatin landscapes between CD4+ and CD8+ αβ-lineage cells that support their effector functions and reveal gene-specific mechanisms that define mature T cells. This resource provides a framework for studying gene regulatory mechanisms that drive normal and malignant human T cell development.