Explore the vast range of titles available.

The transcription factor Foxp3 is essential for the function of regulatory T cells (T reg cells). Rudensky and colleagues show binding of Foxp3 poises target genes for repression and, after activation of T reg cells, recruits the histone methyltransferase Ezh2. The transcription factor Foxp3 is indispensable for the ability of regulatory T cells (T reg cells) to suppress fatal inflammation. Here we characterized the role of Foxp3 in chromatin remodeling and the regulation of gene expression in actively suppressive T reg cells in an inflammatory setting. Although genome-wide occupancy of regulatory elements in DNA by Foxp3 was similar in resting T reg cells and those activated in vivo , Foxp3-bound enhancer elements in the DNA were poised for repression only in activated T reg cells. Following activation, Foxp3-bound sites showed diminished accessibility of chromatin and selective deposition of histone H3 trimethylated at Lys27 (H3K27me3), which was associated with recruitment of the histone methyltransferase Ezh2 and downregulation of the expression of nearby genes. Thus, Foxp3 poises its targets for repression by facilitating the formation of repressive chromatin in T reg cells upon their activation in response to inflammatory cues.

Glucose availability is limiting in tumor environments. Zou and colleagues show that reduced glycolytic metabolism in T cells within tumors suppresses expression of the methyltransferase EZH2, which limits production of antitumor effector molecules and enhances T cell apoptosis. Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA–mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2 + CD8 + T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.

T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8 + T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhances Polycomb repressor complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2-associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrates a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8 + T cell antitumor responses. These effects rely on Phf19 histone-binding capacity, which is critical for the recruitment of PRC2 to the target chromatin. These findings establish the miR-155–Phf19–PRC2 as a pivotal axis regulating CD8 + T cell differentiation, thereby paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8 + T cell fate. The inability of T cells to properly mount anti-tumour immunity underlies failed cancer immune surveillance or therapy. Here the authors show that a microRNA, miR-155, suppresses Ship1 phosphatase expression to modulate epigenetic reprogramming of CD8 T cell differentiation via the Phf19/PRC2 axis, thereby implicating a novel aspect of cancer immunity regulation.

The roles of EZH2 in various subsets of CD4 + T cells are controversial and its mechanisms of action are incompletely understood. FOXP3-positive Treg cells are a critical helper T cell subset and dysregulation of Treg generation or function results in systemic autoimmunity. FOXP3 associates with EZH2 to mediate gene repression and suppressive function. Herein, we demonstrate that deletion of Ezh2 in CD4 T cells resulted in reduced numbers of Treg cells in vivo and differentiation in vitro and an increased proportion of memory CD4 T cells in part due to exaggerated production of effector cytokines. Furthermore, we found that both Ezh2- deficient Treg cells and T effector cells were functionally impaired in vivo : Tregs failed to constrain autoimmune colitis and T effector cells neither provided a protective response to T. gondii infection nor mediated autoimmune colitis. The dichotomous function of EZH2 in regulating differentiation and senescence in effector and regulatory T cells helps to explain the apparent existing contradictions in literature.

T-cell development is accompanied by epigenetic changes that ensure the silencing of stem cell-related genes and the activation of lymphocyte-specific programmes. How transcription factors influence these changes remains unclear. We show that the Ikaros transcription factor forms a complex with Polycomb repressive complex 2 (PRC2) in CD4 − CD8 − thymocytes and allows its binding to more than 500 developmentally regulated loci, including those normally activated in haematopoietic stem cells and others induced by the Notch pathway. Loss of Ikaros in CD4 − CD8 − cells leads to reduced histone H3 lysine 27 trimethylation and ectopic gene expression. Furthermore, Ikaros binding triggers PRC2 recruitment and Ikaros interacts with PRC2 independently of the nucleosome remodelling and deacetylation complex. Our results identify Ikaros as a fundamental regulator of PRC2 function in developing T cells. Haematopoietic stem and progenitor cell-specific genes are epigenetically silenced during T cell differentiation. Here the authors show that Ikaros represses over 500 loci in developing T cells in cooperation with PRC2 and independently of its well established partner NuRD.

Low availability of glucose in tumors negatively affects the activity of tumor-infiltrating T cells. Loss of T cell function under these conditions is mediated by the microRNAs miR-101 and miR-26a, which target expression of the methytransferase EZH2 and thereby diminish the expression of anti-tumor cytokines.

Polycomb group (PcG) proteins, which are conserved from invertebrates to mammals, are associated with epigenetic regulation of many cell fates. The activities of PcG proteins are largely associated with modulation of specific immune reactions. However, no study has attempted to explore the role of Phc2, a subunit of polycomb repressive complex 1, on helper T (Th) cell activation. Presently, Phc2 expression was down-regulated in activated Th cells. The ectopic expression of Phc2 in Th cells inhibited Th cell proliferation and secretion of interleukin-2 from Th cells upon antigen-specific activation. Phc2 may act as a negative regulator that inhibits the activity of Th cells.

Gonadal sex determination and differentiation are controlled by somatic support cells of testes (Sertoli cells) and ovaries (granulosa cells). In testes, the epigenetic mechanism that maintains chromatin states responsible for suppressing female sexual differentiation remains unclear. Here, we show that Polycomb repressive complex 1 (PRC1) suppresses a female gene regulatory network in postnatal Sertoli cells. We genetically disrupted PRC1 function in embryonic Sertoli cells after sex determination, and we found that PRC1-depleted postnatal Sertoli cells exhibited defective proliferation and cell death, leading to the degeneration of adult testes. In adult Sertoli cells, PRC1 suppressed specific genes required for granulosa cells, thereby inactivating the female gene regulatory network. Chromatin regions associated with female-specific genes were marked by Polycomb-mediated repressive modifications: PRC1-mediated H2AK119ub and PRC2-mediated H3K27me3. Taken together, this study identifies a critical Polycomb-based mechanism that suppresses ovarian differentiation and maintains Sertoli cell fate in adult testes.

Treating ovarian cancer in mouse models with inhibitors for the epigenetic regulators EZH2 and DNMT1 increases the expression of the inflammatory chemokines CXCL9 and CXCL10, resulting in enhanced tumour infiltration by effector T cells, and slowed tumour progression. Epigenetic reprograming and cancer immunotherapy The therapeutic response of cancer patients to immunotherapy can be variable. Weiping Zou and colleagues hypothesize that immunoprotective signature genes might be epigenetically silenced in cancer, thereby promoting cancer progression and blunting the clinical response to immunotherapy. To test this idea the authors treated ovarian cancer in mouse models with agents that inhibit the epigenetic regulators EZH2 and DNMT1. They find that inhibition of EZH2 and DNMT1 increases the expression of the inflammatory chemokines CXCL9/10, resulting in enhanced tumour infiltration by effector T cells, and slower tumour progression. Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism 1 . However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (T H 1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade 2 , 3 , 4 and adoptive T-cell transfusion 5 in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8 + T cells and patient outcome. Thus, epigenetic silencing of T H 1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape 6 in cancer and may enhance the clinical efficacy of cancer therapy.

Ezh2 is a protein methylase that epigenetically modifies chromatin. Su and colleagues identify a cytoplasmic role for Ezh2 whereby it controls the extravasation of innate leukocytes through methylation of talin and thereby influences inflammatory responses in vivo. A cytosolic role for the histone methyltransferase Ezh2 in regulating lymphocyte activation has been suggested, but the molecular mechanisms underpinning this extranuclear function have remained unclear. Here we found that Ezh2 regulated the integrin signaling and adhesion dynamics of neutrophils and dendritic cells (DCs). Ezh2 deficiency impaired the integrin-dependent transendothelial migration of innate leukocytes and restricted disease progression in an animal model of multiple sclerosis. Direct methylation of talin, a key regulatory molecule in cell migration, by Ezh2 disrupted the binding of talin to F-actin and thereby promoted the turnover of adhesion structures. This regulatory effect was abolished by targeted disruption of the interactions of Ezh2 with the cytoskeletal-reorganization effector Vav1. Our studies reveal an unforeseen extranuclear function for Ezh2 in regulating adhesion dynamics, with implications for leukocyte migration, immune responses and potentially pathogenic processes.