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&NA; 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 (&agr;KG)‐induced events, in part through changes in DNA and histone methylation states. We further identified a mechanism by which IL‐2‐ and &agr;KG‐sensitive metabolic changes regulated the association of CCCTC‐binding factor (CTCF) with select genomic sites. &agr;KG‐sensitive CTCF sites were often associated with loci containing IL‐2‐ and &agr;KG‐sensitive genome organization patterns and gene expression in T cells. IL‐2‐ and &agr;KG‐sensitive CTCF sites in T cells were also associated with genes from developmental pathways that had &agr;KG‐sensitive expression in embryonic stem cells. The data collectively support a mechanism wherein CTCF serves to translate &agr;KG‐sensitive metabolic changes into context‐dependent differentiation gene programs. Graphical Abstract Figure. No caption available. HighlightsGln‐ and &agr;KG‐sensitive events promote the IL‐2‐sensitive effector‐like gene programIL‐2‐ and &agr;KG‐sensitive events influence DNA and H3K27 methylation in Th1 cellsIL‐2‐ and &agr;KG‐sensitive events regulate CTCF and genome organization in Th1 cells&agr;KG‐sensitive changes in CTCF are interpreted into context‐dependent gene programs &NA; Metabolic 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 &agr;KG‐sensitive metabolic events into context‐dependent differentiation gene programs.