Global Mapping of H3K4me3 and H3K27me3 Reveals Specificity and Plasticity in Lineage Fate Determination of Differentiating CD4⁺ T Cells

Multipotential naive CD4⁺ T cells differentiate into distinct lineages including T helper 1 (Th1), Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4⁺ T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) trimethylation maps in naive, Th1, Th2, Th17, iTreg, and natural Treg (nTreg) cells. We found that although modifications of signature-cytokine genes (Ifng, Il4, and Il17) partially conform to the expectation of lineage commitment, genes encoding transcription factors like Tbx21 exhibit a broad spectrum of epigenetic states, consistent with our demonstration of T-bet and interferon-γ induction in nTreg cells. Our data suggest an epigenetic mechanism underlying the specificity and plasticity of effector and regulatory T cells and also provide a framework for understanding complexity of CD4⁺ T helper cell differentiation.