Unconventional Association of the Polycomb Group Proteins with Cytokine Genes in Differentiated T Helper Cells

Abstract

The cytokine transcription profiles of developing T helper 1 and T helper 2 cells are imprinted and induced appropriately following stimulation of differentiated cells. Epigenetic regulation combines several mechanisms to ensure the inheritance of transcriptional programs. We found that the expression of the polycomb group proteins, whose role in maintaining gene silencing is well documented, was induced during development in both T helper lineages. Nevertheless, the polycomb proteins, YY1, Mel-18, Ring1A, Ezh2, and Eed, bound to the Il4 and Ifng loci in a differential pattern. In contrast to the prevailing dogma, the binding activity of the polycomb proteins in differentiated T helper cells was associated with cytokine transcription. The polycomb proteins bound to the cytokine genes under resting conditions, and their binding was induced dynamically following stimulation. The recruitment of the polycomb proteins Mel-18 and Ezh2 to the cytokine promoters was inhibited in the presence of cyclosporine A, suggesting the involvement of NFAT. Considering their binding pattern at the cytokine genes and their known function in higher order folding of regulatory elements, we propose a model whereby the polycomb proteins, in some contexts, positively regulate gene expression by mediating long-distance chromosomal interactions.

Th2 LCR is essential for regulation of Th2 cytokine genes and for pathogenesis of allergic asthma

“…These factors may in turn recruit other factors such as chromatin-modifying enzymes to the Th2 LCR and other regulatory regions of the Th2 cytokine locus. It has been shown that the ATP-dependent chromatin remodeling factor BRG-1 and Polycomb Group proteins such as YY-1, Mel-18, Ring1A, Ezh2, and Eed are recruited to RHS7, as well as il4 promoter and several regulatory elements in the Th2 cytokine locus (36)(37)(38). These chromatin-modifying factors may induce chromatin remodeling and intra-and interchromosomal interactions.…”

The polycomb repressive complex 2 governs life and death of peripheral T cells

“…27 However, it was also reported that recruitment of Ezh2 was required for both IFN-g and IL-4 production in differentiated Th1 and Th2 cells. 28 The polycomb repressive complex (PRC) proteins form 2 closely related complexes-PRC2 and PRC1. H3K27 trimethylation is catalyzed by the methyltransferases Ezh2 or Ezh1, 29 which are core components of PRC2 along with Suz12 and Eed.…”

The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease

“…27,28 Previous studies demonstrate that IFN-g-producing alloreactive T help (Th)1 effector cells cause damage to the liver and gastrointestinal tract but prevents lung injury mainly induced by IL-4-producing Th2 effector cells. 29,30 To investigate the impact of Ezh2 on effector T-cell differentiation, we recovered donor T cells from BALB/C mice receiving B6 mouse-derived WT and T-KO T cells at various time points after transplantation.…”