CCCTC-Binding Factor Translates Interleukin 2-and α-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs

Despite considerable research connecting cellular metabolism with differentiation decisions, the underlying mechanisms that translate metabolite-sensitive activities into unique gene programs are still unclear. We found that aspects of the interleukin-2 (IL-2)-sensitive effector gene program in CD4(+) and CD8(+) T cells in type 1 conditions (Th1) were regulated by glutamine and alpha-ketoglutarate (alpha KG)-induced events, in part through changes in DNA and histone methylation states. We further identified a mechanism by which IL-2- and alpha KG-sensitive metabolic changes regulated the association of CCCTC-binding factor (CTCF) with select genomic sites. alpha KG-sensitive CTCF sites were often associated with loci containing IL-2- and alpha KG-sensitive genome organization patterns and gene expression in T cells. IL-2-and alpha KG-sensitive CTCF sites in T cells were also associated with genes from developmental pathways that had alpha KG-sensitive expression in embryonic stem cells. The data collectively support a mechanism wherein CTCF serves to translate alpha KG-sensitive metabolic changes into context-dependent differentiation gene programs.