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MLL4 is an essential subunit of the H3K4 methylation complexes. We report that MLL4 deficiency compromised regulatory T (Treg) cell development and resulted in substantial decreases in H3K4me1 and chromatin interaction at putative enhancers, a remarkable portion of which were not direct targets of MLL4 but were enhancers that interact with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the MLL4-unbound enhancers correlated with MLL4 binding at distant-interacting regions. Deletion of an upstream MLL4 binding site reduced H3K4me1 at the Foxp3 regulatory elements looped to the MLL4 binding site and compromised both thymic Treg and inducible Treg cell differentiation. We show that MLL4 catalyzed H3K4 methylation at distant unbound enhancers via chromatin looping, thus providing a new mechanism of regulating T cell enhancer landscape and impacting Treg cell differentiation.

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Most mammalian genomes are diploid and previous studies have extensively investigated the average epigenetic profiles of homologous chromosomes. Here we use hybrid mice to distinguish the epigenetic status and three-dimensional organization of homologous chromosomes. We generated Hi-C, ChIP-seq and RNA-seq datasets from CD4 T cells of B6, Cast and hybrid mice, respectively, and systematically analyzed the 3D nucleus organization and epigenetic regulation. Our data indicate that the inter-chromosomal interaction patterns between homologous chromosomes are similar and the similarity is highly correlated with their allelic co-expression levels. Construction of 3D nucleus based on allele-specific interaction frequency revealed symmetric positioning of homologous chromosomes in the 3D nuclear space. The inter-chromosomal interactions at centromeres are significantly weaker than those at telomeres, indicating positioning of centromeres toward the inside of chromosome territories and telomeres toward the surface of chromosome territories. The majority A|B compartments or topologically associated domains (TADs) are consistent between B6 and Cast. We found 58% of the haploids in hybrids maintain their parental compartment status at B6/Cast divergent compartments due to cis-effect. About 95% of the trans-effected B6/Cast divergent compartments converge to same compartment status potentially due to a shared cellular environment. We found the differentially expressed genes between the two haploids in hybrid were associated with either genetic associated cis-effects or epigenetic associated trans-effects. The widespread epigenetic differences between B6 and Cast suggest that .

Summary Significant progress has been made during the past years in our understanding of the mechanisms that control the differentiation of naïve CD4+ T cells into effector T‐cell subsets with distinct functional properties. Previous work allowed the identification of key molecules involved in regulating this highly complex process, such as cytokines and their receptors, signal transducers and transcription factors. More recently, the emphasis of research in this field has been to elucidate how the multiplicity of signals is integrated to shape a T helper subset‐specific gene‐expression program controlling differentiation and effector functions. In this review we will highlight advances that have been made in unravelling the genetic and epigenetic networks controlling differentiation of naïve CD4+ T cells into interferon‐γ(IFN‐γ)‐secreting T helper type 1 (Th1) cells.

BackgroundNatural killer (NK)T cells and conventional T cells share phenotypic characteristic however they differ in transcription factor requirements and functional properties. The role of histone modifying enzymes in conventional T cell development has been extensively studied, little is known about the function of enzymes regulating histone methylation in NKT cells.ResultsWe show that conditional deletion of histone demethylases UTX and JMJD3 by CD4-Cre leads to near complete loss of liver NKT cells, while conventional T cells are less affected. Loss of NKT cells is cell intrinsic and not due to an insufficient selection environment. The absence of NKT cells in UTX/JMJD3-deficient mice protects mice from concanavalin A‐induced liver injury, a model of NKT‐mediated hepatitis. GO‐analysis of RNA-seq data indicates that cell cycle genes are downregulated in UTX/JMJD3-deleted NKT progenitors, and suggest that failed expansion may account for some of the cellular deficiency. The phenotype appears to be demethylase‐dependent, because UTY, a homolog of UTX that lacks catalytic function, is not sufficient to restore their development and removal of H3K27me3 by deletion of EZH2 partially rescues the defect.ConclusionsNKT cell development and gene expression is sensitive to proper regulation of H3K27 methylation. The H3K27me3 demethylase enzymes, in particular UTX, promote NKT cell development, and are required for effective NKT function.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-017-0152-8) contains supplementary material, which is available to authorized users.

T-bet is a key regulator controlling Th1 cell development. This factor is not expressed in naive CD4+ T cells, and the mechanisms controlling expression of T-bet are incompletely understood. In this study, we defined regulatory elements at the human T-bet locus and determined how signals originating at the TCR and at cytokine receptors are integrated to induce chromatin modifications and expression of this gene during human Th1 cell differentiation. We found that T cell activation induced two strong DNase I-hypersensitive sites (HS) and rapid histone acetylation at these elements in CD4+ T cells. Histone acetylation and T-bet expression were strongly inhibited by cyclosporine A, and we detected binding of NF-AT to a HS in vivo. IL-12 and IFN-γ signaling alone were not sufficient to induce T-bet expression in naive CD4+ T cells, but enhanced T-bet expression in TCR/CD28-stimulated cells. We detected a third HS 12 kb upstream of the mRNA start site only in developing Th1 cells, which was bound by IL-12-induced STAT4. Our data suggest that T-bet locus remodeling and gene expression are initiated by TCR-induced NF-AT recruitment and amplified by IL-12-mediated STAT4 binding to distinct distal regulatory elements during human Th1 cell differentiation.