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Regulation of T helper cell differentiation by the interplay between histone modification and chromatin interaction

ABSTRACT: The development and function of the immune system are controlled by temporospatial gene expression programs, which are regulated by cis-regulatory elements, chromatin structure, and trans-acting factors. In this study, we cataloged the dynamic histone modifications and chromatin interactions at regulatory regions during T helper (Th) cell differentiation. Our data revealed that the H3K4me1 landscape established by MLL4 in naive CD4+ T cells is critical for restructuring the regulatory interaction network and orchestrating gene expression during the early phase of Th differentiation. GATA3 plays a crucial role in further configuring H3K4me1 modification and the chromatin interaction network during Th2 differentiation. Furthermore, we demonstrated that HSS3-anchored chromatin loops function to restrict the activity of the Th2 locus control region (LCR), thus coordinating the expression of Th2 cytokines. Our results provide insights into the mechanisms of how the interplay between histone modifications, chromatin looping, and trans-acting factors contributes to the differentiation of Th cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE237916 | GEO | 2024/03/01

REPOSITORIES: GEO

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Project description:Regulatory T cells (Treg) contribute to the crucial immunological processes of self-tolerance and immune homeostasis. However, the mechanisms underlying Treg function and cell fate decisions to differentiate between Treg and conventional T cells (Tconv) remain to be fully elucidated, especially at the histone modification level. Covalent modifications of histones establish and maintain chromatin structure, and regulate gene transcription events by facilitating access to cis-elements by trans-acting factors during mammalian development and cellular differentiation. We aimed to investigate the role of the methylation form of histone modification as related to Treg function and phenotype. High-resolution maps of the genome-wide distribution of monomethylated histone H3 lysine 4, H3K4me1, and the trimethylated form H3K4me3 were generated for human activated conventional CD4+CD25+FOXP3- T cells (aTconv) and CD4+CD25+FOXP3+ regulatory T cells (Treg) by sequencing using the Solexa 1G Genetic Analyzer. We found 2115 H3K4me3 regions corresponding to proximal promoter regions; the genes associated with these regions in Treg cells included the crucial transcription factor forkhead box P3 (FOXP3) and the chemokine receptor CCR7. We also identified 41024 Treg cell type-specific H3K4me1 regions. The majority of the H3K4me1 regions differing between the Treg and aTconv cells were located at promoter-distal sites, some of which were selected and consolidated to further examine enhancer activity in in vitro reporter gene assays. The findings from our study provide a comprehensive genome-wide dataset of lineage-specific H3K4me1 and H3K4me3 patterns in Treg and aTconv cells, which may control the differentiation decision, lineage commitment and cell type-specific gene regulation. This basic principle is likely not confined to the two closely-related T cell populations, but may apply generally to somatic cell lineages in adult organisms. Genome-wide distribution of monomethylated histone H3 lysine 4, H3K4me1, and the trimethylated form H3K4me3 in human activated conventional CD4+CD25+FOXP3- T cells (aTconv) and CD4+CD25+FOXP3+ regulatory T cells (Treg) (5 samples in total)

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Regulation of T helper cell differentiation by the interplay between histone modification and chromatin interaction

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