CTCF translates IL-2- and αKG-sensitive metabolic changes in T cells into context-dependent differentiation gene programs [ChIP-Seq]

We found that aspects of the IL-2-sensitive effector gene program in CD4+ Th1 and CD8+ Tc1 cells are regulated by glutamine and alpha-ketoglutarate (αKG)-induced events, in part through changes in DNA and histone methylation states. We further identified a novel mechanism by which IL-2- and αKG-sensitive metabolic changes regulate the association of CTCF with select genomic sites. αKG-sensitive CTCF sites were often associated with loci containing IL-2- and αKG-sensitive genome organization patterns and gene expression in T cells. Surprisingly, IL-2- and αKG-sensitive CTCF sites in T cells were also associated with genes from developmental pathways that had αKG-sensitive expression in ES cells. The data collectively support a novel mechanism wherein CTCF serves to translate αKG-sensitive metabolic changes into context-dependent differentiation gene programs. We performed a ChIP-seq analysis examining H3K27me3 states in CD4+ Th1 cells maintained in high IL-2, low IL-2, or low IL-2 with αKG. We also performed a CTCF ChIP-seq analysis with CD4+ Th1 cells maintained in high IL-2, low IL-2, or low IL-2 with αKG to define the sites associated with CTCF in each condition. In addition, we performed an H3K27Ac ChIP-seq analysis with Th1 cells maintained in high IL-2, low IL-2, or low IL-2 with αKG to examine potential enhancer regions in each condition.