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Abstract

The epigenetic landscape of interleukin 15 (IL15) signaling in TCRαβ+CD3+CD8+ intestinal intraepithelial lymphocytes (IELs) has remained unknown despite well characterized molecular pathways downstream of IL15. By using short termed IEL cell lines and various sequencing techniques targeted at the epigenetic landscape (ATAC-Seq, histone CHIP-Seq, and 5hmC Seq), we demonstrated that during IL15 signaling, the chromatin accessibility and histone marks (H3K4me1, H3K4me3, H3K27Ac, H3K27me3) remained stable while the 5hmC landscape changed dynamically in complex temporal patterns. Dynamic 5hmC regions (DHMRs) locate mostly at the enhancer sites, and genes associated with DHMRs are more likely to be differentially expressed. The loss of 5hmC is associated with early induced genes while the gain of 5hmC is associated with repressed genes. By knocking down Tet2, we demonstrated the roles of Tet2 in the generation of these DHMRs and in the transcriptional control of a subset of IL15 regulated genes, mainly cell cycle, defense response and type 1 IFN related gene sets. Altogether, these results suggested that IL15 uses a combination of preset epigenetic landscape and altering epigenetic landscape to promote large transcriptional changes in IELs and carries out its diverse biological functions.

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