Cutting edge: changes in histone acetylation at the IL-4 and IFN-gamma loci accompany Th1/Th2 differentiation.
ABSTRACT Peripheral T cell differentiation is accompanied by chromatin changes at the signature cytokine loci. Using chromatin immunoprecipitation we demonstrate that profound increases in histone acetylation occur at the IFN-gamma and IL-4 loci during Th1/Th2 differentiation. These changes in histone acetylation status are locus and lineage specific, and are maintained by the transcription factors Tbet and GATA3 in a STAT-dependent manner. Our results suggest a model of cytokine locus activation in which TCR signals initiate chromatin remodeling and locus opening in a cytokine-independent fashion. Subsequently, cytokine signaling reinforces polarization by expanding and maintaining the accessible state at the relevant cytokine locus (IL-4 or IFN-gamma). In this model, GATA3 and Tbet serve as transcriptional maintenance factors, which keep the locus accessible to the transcriptional machinery.
Full-textDOI: · Available from: Richard A Flavell, Jul 01, 2015
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ABSTRACT: In order to develop the most effective T helper type-1 (Th1) immunity, naïve CD4(+) T cells must acquire the capacity to express IFN-γ while silencing T helper type-2 (Th2) cytokine-producing potential. An Il4 gene silencer has been described. However, it is not completely understood how the silencer works. In this study, we examine whether IFN-γ can suppress permissive chromatin remodeling of regulatory region of the Il4 gene. We demonstrate that IFN-γ suppresses H3K4 dimethylation at the intronic enhancer region of the Il4 gene. The IFN-γ-mediated suppression of permissive chromatin remodeling is IFN-γ receptor-, STAT1-, and T-bet-dependent. Our study reveals a novel mechanism of how Th1 cells silence the Il4 gene.Cytokine 03/2013; 62(1). DOI:10.1016/j.cyto.2013.02.010 · 2.87 Impact Factor
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ABSTRACT: The myelodysplastic syndromes (MDS) constitute a group of heterogeneous clonal haemopoietic stem cell disorders, characterized by ineffective and dysplastic haematopoiesis with varying degrees of peripheral cytopenia. Low-risk MDS is characterized by increased apoptosis in the bone marrow (BM) with autoimmune characteristics whereas the advanced or high-risk stages involve immune evasion and secondary DNA damage, giving cells growth potential to progress into acute myeloid leukaemia (AML). Nevertheless, the causes of MDS remain poorly defined and it is not clear how the disease progresses from an early stage to advanced MDS and AML. Although there are clear indications for a role of the immune system, the exact mechanism by which the immune response contributes to the progression is not yet clear. New insights into the pathophysiology of MDS with regard to the immune system will be instrumental for the development of novel patient-oriented therapies. This review is focused on the role of immune responses in MDS and the implications for the development of novel immune therapies.British Journal of Haematology 06/2011; 153(5):568-81. DOI:10.1111/j.1365-2141.2011.08683.x · 4.96 Impact Factor
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ABSTRACT: We showed previously that murine naive CD4(+) T cells and T(H)1 cell clones express the beta2-adrenergic receptor (β(2)AR), while T(H)2 cell clones do not. We report here that naive CD4(+) T cells that differentiated for 1-5 days under T(H)1 driving conditions increased β(2)AR gene expression, while cells cultured under T(H)2 driving conditions decrease β(2)AR gene expression. Chromatin immunoprecipitation revealed that the increase in β(2)AR gene expression in T(H)1 cells is mediated by an increase in histone 3 (H3) and H4 acetylation, as well as an increase in histone 3 lysine 4 (H3K4) methylation. Conversely, the decrease in β(2)AR gene expression in T(H)2 cells is mediated by a decrease in H3 and H4 acetylation and a decrease in H3K4 methylation, as well as an increase H3K9 and H3K27 methylation. The histone changes could be detected as early as 3 days of differentiating conditions. Genomic bisulfite sequencing showed that the level of methylated CpG dinucleotides within the promoter of the β(2)AR gene was increased in T(H)2 cells as compared to naive and T(H)1 cells. Collectively, these results suggest that epigenetic mechanisms mediate maintenance and repression, respectively, of the β(2)AR gene expression in T(H)1- and T(H)2-driven cells, providing a potential mechanism by which the level of β(2)AR expression might be modulated pharmacologically within immune cells and other cell types in which the expression profile may change during a disease process.Brain Behavior and Immunity 10/2010; 25(3):408-15. DOI:10.1016/j.bbi.2010.10.019 · 6.13 Impact Factor