CTCF translates IL-2- and αKG-sensitive metabolic changes in T cells into context-dependent differentiation gene programs [HiC-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. To address whether IL-2- and aKG-sensitive CTCF binding events might influence genome organization, we performed an in situ Hi-C analysis on CD4+ T cells polarized in Th1 conditions and maintained in high IL-2, low IL-2, or low IL-2 with aKG. Data from the Hi-C analysis were analyzed to define changes in genome organization associated with each condition.