miR-155 Activates Cytokine Gene Expression in Th17 Cells by Regulating the DNA-Binding Protein Jarid2 to Relieve Polycomb-Mediated Repression

Escobar, Thelma M.; Kanellopoulou, Chrysi; Kugler, David; Kilaru, Gokhul; Nguyen, Cuong K.; Nagarajan, Vijayaraj; Bhairavabhotla, Ravikiran; Northrup, Daniel; Zahr, Rami; Burr, Patrick; Liu, Xiuhuai; Zhao, Keji; Sher, Alan; Janković, Dragana; Zhu, Jinfang; Muljo, Stefan A.

doi:10.1016/j.immuni.2014.03.014

Cited by 169 publications

(161 citation statements)

References 59 publications

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“…During in vitro polarization, the activity of EZH2 also prevents plasticity between T H 1 and T H 2 cell subsets and supports pT Reg cell generation by inhibiting IFNγ expression 153,154 . However, T H 17 cell polarization seems to be impaired by increased PRC2 activity 154,155 . Interestingly, in cells lacking H3K27 KDM JMJD3 (also known as KDM6B), T H 17 cell polarization is enhanced, and many polarized T cell subsets exhibit enhanced stability 156 .…”

Section: Inhibiting Dna Accessibility With Heterochromatinmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Section: Inhibiting Dna Accessibility With Heterochromatinmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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“…Jarid2 is a chromatin-binding protein that silences transcription by recruiting PRC2 (polycomb repressive complex 2), which in turn mediates the trimethylation of histone 3 at lysine 27 (H3K27me3) [85]. In the absence of miR-155, the increased widespread recruitment of Jarid2 was shown to match the increase in H3K27me3 marks [85] (Fig.…”

Section: Mirna Regulation Of Il-2mentioning

confidence: 99%

“…This contrasted with previous reports of miR-155 involvement in Helicobacter pylori infection and in EAE, where miR-155 had been suggested to be required for the development of both Th17-and Th1-cell subsets [87,88]. Further studies are required to elucidate the mechanisms behind this differential impact of miR-155 under different infection and inflammation models.While Th17-driving transcription factors, such as RORγt, BATF, IRF4, were shown not to be targets of miR-155, Jarid2 (Jumonji, AT rich interactive domain 2), a previously described miR-155 target [89], was shown to accumulate in T cells in the absence of miR-155 [85]. Jarid2 is a chromatin-binding protein that silences transcription by recruiting PRC2 (polycomb repressive complex 2), which in turn mediates the trimethylation of histone 3 at lysine 27 (H3K27me3) [85].…”

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confidence: 90%

“…miR-155 is highly expressed in the Th17-cell subset, both in humans and in mice, and its deficiency has been shown to lower the expression of IL-17A and IL-22, as well as IL-9 and IL-10 [85,86]. In a murine model of Toxoplasma gondii infection, miR-155 was shown to be required for cytokine expression by Th17 cells and for Treg-cell homeostasis, but not for the Th1 response against the parasite [85]. This contrasted with previous reports of miR-155 involvement in Helicobacter pylori infection and in EAE, where miR-155 had been suggested to be required for the development of both Th17-and Th1-cell subsets [87,88].…”

Section: Mirna Regulation Of Il-17 and Type 17 Associated Factorsmentioning

confidence: 99%

“…2). However, these results has been controversial, as subsequent studies could not detect miR-326 in neither murine nor human Th17 cells, and no differential expression of miR-326 was identified in the T cells of MS patients versus healthy controls [9], [83], [84].In a recent study, Muljo and colleagues described a role for miR-155 within a complex network regulating Th17 cytokines [85]. miR-155 is highly expressed in the Th17-cell subset, both in humans and in mice, and its deficiency has been shown to lower the expression of IL-17A and IL-22, as well as 86].…”

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confidence: 99%

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Cross‐regulation between cytokine and microRNA pathways in T cells

et al. 2015

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microRNA (miRNA) mediated regulation of protein expression has emerged as an important mechanism in T-cell physiology, from development and survival to activation, proliferation, and differentiation. One of the major classes of proteins involved in these processes are cytokines, which are both key input signals and major products of T-cell function. Here, we summarize the current data on the molecular cross-talk between cytokines and miRNAs: how cytokines regulate miRNA expression, and how specific miRNAs control cytokine production in T cells. We also describe the inflammatory consequences of deregulating the miRNA/cytokine axis in mice and humans. We believe this topical area will have key implications for immune modulation and treatment of autoimmune pathology. Keywords:Cytokines r Inflammation r miRNA r T cells microRNAs as regulators of protein expressionBiological processes require the integration of environmental stimuli at the level of gene expression. The robustness of genetic networks depends on the distinction between physiological responses (to particular cues) and biological "noise" (stochastic variations), which can be achieved, for example, by establishing feed-forward transcriptional loops. Over the past two decades, a new mechanism that interacts with transcriptional loops and sets additional thresholds, which enable cells to filter physiological signals from noise has emerged; this mechanism regulates gene expression at the posttranscriptional level and relies on microRNAs (miRNAs; reviewed in [1]). These are an abundant class of evolutionarily conserved small noncoding (untranslated) RNA species that control target mRNA stability, degradation, and translation, thus affecting the majority of mammalian genes [2].Correspondence: Dr. Anita Q. Gomes e-mail: anitagomes@medicina.ulisboa.ptIn the conventional miRNA biogenesis pathway, RNA polymerase II transcribed pri-miRNAs are processed by the nuclear RNase III enzyme Drosha (complexed with DGCR8) to generate 60-70 nt stem-loop intermediates, the pre-miRNAs, that are further processed into 19-24mers in the cytoplasm by another key RNase III, Dicer. Mature miRNAs are then incorporated into RNAinduced silencing complexes, whose core components are proteins of the Argonaute family (Ago1-4), which use the 5 end (nucleotides 2-8) "seed sequence" of the miRNA to recognize complementary mRNA transcripts (mostly in their 3 untranslated region) for deadenylation or inhibition of translation, ultimately resulting in mRNA decapping and decay (reviewed in [3,4]).Unique spatial and temporal expression patterns in distinct hematopoietic cell lineages are suggestive of multiple roles for miRNAs in hematopoiesis, self-tolerance, and in immune responses, which have been explored over the past decade (reviewed in [5,6]). Over a 100 different miRNAs have been shown to be expressed by cells of the immune system, where * These authors contributed equally to this work as first authors. * * These authors contributed equally to this work as last authors.C 2015 WILEY-VCH Ve...

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