CTCF translates IL-2- and aKG-sensitive metabolic changes in T cells into context-dependent differentiation gene programs [ATAC-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 (aKG)-induced events, in part through changes in DNA and histone methylation states. We further identified a novel mechanism by which IL-2- and aKG-sensitive metabolic changes regulate the association of CTCF with select genomic sites. aKG-sensitive CTCF sites were often associated with loci containing IL-2- and aKG-sensitive genome organization patterns and gene expression in T cells. Surprisingly, IL-2- and aKG-sensitive CTCF sites in T cells were also associated with genes from developmental pathways that had aKG-sensitive expression in ES cells. The data collectively support a novel mechanism wherein CTCF serves to translate aKG-sensitive metabolic changes into context-dependent differentiation gene programs. Overall design: Antigen specific CD8+ T cells were generated during the course of an influenza infection in mice. 7-9 days after the initial influenza infection, tetramer positive NP antigen specific or OTI specific CD8+ T cells were sorted into CD25high or CD25low populations.