Chisolm Danielle A, Savic Daniel, Moore Amanda J, Ballesteros-Tato Andre, León Beatriz, Crossman David K, Murre Cornelis, Myers Richard M, Weinmann Amy S
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
Immunity. 2017 Aug 15;47(2):251-267.e7. doi: 10.1016/j.immuni.2017.07.015.
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.
尽管有大量研究将细胞代谢与分化决定联系起来，但将代谢物敏感活性转化为独特基因程序的潜在机制仍不清楚。我们发现，在1型条件（Th1）下，CD4和CD8 T细胞中白细胞介素-2（IL-2）敏感效应基因程序的某些方面受谷氨酰胺和α-酮戊二酸（αKG）诱导的事件调控，部分是通过DNA和组蛋白甲基化状态的变化。我们进一步确定了一种机制，通过该机制，IL-2和αKG敏感的代谢变化调节CCCTC结合因子（CTCF）与特定基因组位点的关联。αKG敏感的CTCF位点通常与含有IL-2和αKG敏感基因组组织模式及T细胞基因表达的基因座相关联。T细胞中IL-2和αKG敏感的CTCF位点也与胚胎干细胞中具有αKG敏感表达的发育途径中的基因相关联。这些数据共同支持了一种机制，即CTCF将αKG敏感的代谢变化转化为依赖于上下文的分化基因程序。
