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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 (αKG)-induced events, in part through changes in DNA and histone methylation states. We further identified a mechanism by which IL-2- and αKG-sensitive metabolic changes regulated the association of CCCTC-binding factor (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. IL-2- and αKG-sensitive CTCF sites in T cells were also associated with genes from developmental pathways that had αKG-sensitive expression in embryonic stem cells. The data collectively support a mechanism wherein CTCF serves to translate αKG-sensitive metabolic changes into context-dependent differentiation gene programs.Gln- and αKG-sensitive events promote the IL-2-sensitive effector-like gene programIL-2- and αKG-sensitive events influence DNA and H3K27 methylation in Th1 cellsIL-2- and αKG-sensitive events regulate CTCF and genome organization in Th1 cellsαKG-sensitive changes in CTCF are interpreted into context-dependent gene programsMetabolic states dynamically change during cellular differentiation, but it is currently unclear how changes in metabolism mechanistically regulate differentiation gene programs. Chisolm et al. define a mechanism by which CTCF translates IL-2- and αKG-sensitive metabolic events into context-dependent differentiation gene programs.