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

Publication date: 15 August 2017
Source:Immunity, Volume 47, Issue 2
Author(s): Danielle A. Chisolm, Daniel Savic, Amanda J. Moore, Andre Ballesteros-Tato, Beatriz León, David K. Crossman, Cornelis Murre, Richard M. Myers, Amy S. Weinmann
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.

Graphical abstract

Teaser

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 αKG-sensitive metabolic events into context-dependent differentiation gene programs.


http://ift.tt/2wklJL5