Jarid2 Links MicroRNA and Chromatin in Th17 Cells
2014; Cell Press; Volume: 40; Issue: 6 Linguagem: Inglês
10.1016/j.immuni.2014.06.004
ISSN1097-4180
Autores Tópico(s)Cancer-related molecular mechanisms research
ResumoIn this issue of Immunity, Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar bring microRNAs and chromatin together by showing how activation-induced miR-155 targets the chromatin protein Jarid2 to regulate proinflammatory cytokine production in T helper 17 cells. In this issue of Immunity, Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar bring microRNAs and chromatin together by showing how activation-induced miR-155 targets the chromatin protein Jarid2 to regulate proinflammatory cytokine production in T helper 17 cells. MicroRNAs are small noncoding RNAs that control gene expression by destabilizing protein-coding mRNAs and reducing their translation. The microRNA miR-155 is derived from the non-protein-coding transcript of Bic, an oncogene that promotes the development of B cell lymphomas in mice and humans. miR-155 is of interest to immunologists because it is induced by signals that activate T cells, B cells and antigen-presenting cells, and regulates many aspects of the immune response such as the germinal center reaction and the differentiation of T regulatory (Treg) cells and CD4+ T helper (Th) cells (Thai et al., 2007Thai T.H. Calado D.P. Casola S. Ansel K.M. Xiao C. Xue Y. Murphy A. Frendewey D. Valenzuela D. Kutok J.L. et al.Science. 2007; 316: 604-608Crossref PubMed Scopus (1263) Google Scholar, O’Connell et al., 2010O’Connell R.M. Kahn D. Gibson W.S. Round J.L. Scholz R.L. Chaudhuri A.A. Kahn M.E. Rao D.S. Baltimore D. Immunity. 2010; 33: 607-619Abstract Full Text Full Text PDF PubMed Scopus (719) Google Scholar, Oertli et al., 2011Oertli M. Engler D.B. Kohler E. Koch M. Meyer T.F. Müller A. J. Immunol. 2011; 187: 3578-3586Crossref PubMed Scopus (126) Google Scholar, Lu et al., 2009Lu L.F. Thai T.H. Calado D.P. Chaudhry A. Kubo M. Tanaka K. Loeb G.B. Lee H. Yoshimura A. Rajewsky K. Rudensky A.Y. Immunity. 2009; 30: 80-91Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar, Kohlhaas et al., 2009Kohlhaas S. Garden O.A. Scudamore C. Turner M. Okkenhaug K. Vigorito E. J. Immunol. 2009; 182: 2578-2582Crossref PubMed Scopus (317) Google Scholar). In previous studies, miR-155 was required for the differentiation of inflammatory Th1 and Th17 cells in experimental autoimmune encephalomyelitis (O’Connell et al., 2010O’Connell R.M. Kahn D. Gibson W.S. Round J.L. Scholz R.L. Chaudhuri A.A. Kahn M.E. Rao D.S. Baltimore D. Immunity. 2010; 33: 607-619Abstract Full Text Full Text PDF PubMed Scopus (719) Google Scholar) and Helicobacter pylori infection (Oertli et al., 2011Oertli M. Engler D.B. Kohler E. Koch M. Meyer T.F. Müller A. J. Immunol. 2011; 187: 3578-3586Crossref PubMed Scopus (126) Google Scholar). Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar now demonstrate that both Th1 and Th17 cells develop during Toxoplasma gondii infections in miR-155-deficient mice. However, miR-155-deficient CD4+RORγt+ cells are defective in the expression of Il22, Il10, Il9, Il17f, and Il17a. Although microRNAs are posttranscriptional repressors, they can facilitate the transcription of genes, for example through the posttranscriptional repression of a negative regulator of the genes in question. Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar therefore searched for miR-155 targets that might repress cytokine genes. The leading candidate, Jarid2, is the founding member of the Jumonji family of chromatin modifiers. These proteins remove methyl groups from lysine residues in histone tails, and this histone demethylase activity is important for the regulation of gene expression. In contrast to other Jumonji proteins, Jarid2 has amino acid substitutions in its catalytic domain that abolish histone demethylase activity. Although catalytically inactive, Jarid2 is nevertheless important for embryonic development and for embryonic stem cell (ESC) differentiation, suggesting that in relinquishing its histone demethylase activity, Jarid2 might have acquired novel and non-redundant functions. Exactly what these are remains enigmatic, but Jarid2 associates with the polycomb repressive complex 2 (PRC2) in a range of different cell types, including ESCs and thymocytes (Landeira and Fisher, 2011Landeira D. Fisher A.G. Trends Cell Biol. 2011; 21: 74-80https://doi.org/10.1016/j.tcb.2010.10.004Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). First discovered as a regulator of Hox genes in Drosophila, polycomb repressive complexes regulate cellular differentiation and gene expression by modifying the state of chromatin (Margueron and Reinberg, 2011Margueron R. Reinberg D. Nature. 2011; 469: 343-349Crossref PubMed Scopus (2229) Google Scholar). In this way, polycomb proteins contribute to gene regulatory events from the poising of lineage-specific genes in pluripotent ESCs to Th cell differentiation (Landeira and Fisher, 2011Landeira D. Fisher A.G. Trends Cell Biol. 2011; 21: 74-80https://doi.org/10.1016/j.tcb.2010.10.004Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, Tumes et al., 2013Tumes D.J. Onodera A. Suzuki A. Shinoda K. Endo Y. Iwamura C. Hosokawa H. Koseki H. Tokoyoda K. Suzuki Y. et al.Immunity. 2013; 39: 819-832https://doi.org/10.1016/j.immuni.2013.09.012Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). At the molecular level, Jarid2 promotes the recruitment of PRC2 to its target genes (Figure 1). There is disagreement about whether Jarid2 also regulates the methyltransferase activity of PRC2 (Landeira and Fisher, 2011Landeira D. Fisher A.G. Trends Cell Biol. 2011; 21: 74-80https://doi.org/10.1016/j.tcb.2010.10.004Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). However, Jarid2 deficiency is not thought to derepress PRC2 target genes. Rather, many polycomb target genes show reduced expression and impaired recruitment of RNA polymerase II in Jarid2-deficient ESCs. In contrast to PRC2-deficient ESCs, Jarid2-deficient ESCs have a severe differentiation block, and it has therefore been argued that Jarid2 might have a role independent of conventional PCR2 components (Landeira and Fisher, 2011Landeira D. Fisher A.G. Trends Cell Biol. 2011; 21: 74-80https://doi.org/10.1016/j.tcb.2010.10.004Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). The work of Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar links miR-155-mediated posttranscriptional regulation of Jarid2 (and probably other miR-155 targets) to the transcriptional regulation of cytokine genes in Th17 cells (Figure 1). Although the paper does not directly demonstrate that miR-155 targets Jarid2 (e.g., by mutating putative miR-155 binding sites in the Jarid2 3′UTR), this assertion is supported by computational predictions and independent experimental studies (Bolisetty et al., 2009Bolisetty M.T. Dy G. Tam W. Beemon K.L. J. Virol. 2009; 83: 12009-12017https://doi.org/10.1128/JVI.01182-09Crossref PubMed Scopus (89) Google Scholar). Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar find Jarid2 mRNA and protein expression elevated approximately 2-fold in miR-155-deficient Th17 and Treg cells. Such a moderate increase is not unexpected (microRNAs typically act as fine tuners rather than on/off switches) but raises the question how the dosage of a chromatin protein can explain the regulation of cytokine genes in Th17 cells. To explore the link between Jarid2 and reduced Il22 expression, Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar polarize control and miR-155-deficient Th17 cells in vitro. They observe that the production of interleukin-17 (IL-17), but not IL-22, by miR-155-deficient Th17 cells is restored by exogenous IL-1β, a factor that promotes Th17 cytokine expression. Chromatin immunoprecipitation experiments showed increased signal for Jarid2, the PRC2 component Suz12, and the repressive histone modification H3K27me3 at the Il22 locus in miR-155-deficient Th17 cells. Consistent with lower Il22 expression in the absence of miR-155, the Il22 promoter showed reduced occupancy by RNA Polymerase II. These observations are consistent with a scenario where the loss of miR-155 from Th17 cells results in increased Jarid2 expression, Jarid2 binding and PRC2 recruitment to the Il22 locus, increased repressive H3K27me3 histone modifications, reduced RNA polymerase II activity, and reduced Il22 expression (Figure 1). This might be somewhat idealized and at least in ESCs the situation is more complex, as Jarid2 promotes the recruitment not only of PRC2 but also of RNA polymerase II to a set of developmental regulator genes (Landeira and Fisher, 2011Landeira D. Fisher A.G. Trends Cell Biol. 2011; 21: 74-80https://doi.org/10.1016/j.tcb.2010.10.004Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). If increased expression of Jarid2 in miR-155-deficient Th17 cells is responsible for impaired Th17 cytokine expression, then cytokine expression should be restored when one or both copies of the Jarid2 gene are deleted. Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar find that this prediction is partially upheld. Conditional deletion of Jarid2 restores the expression of Il17a in miR-155-deficient Th17 cells but does not rescue Il22. Because Jarid2 does not directly bind Il17 loci, restoration of IL-17 expression is indirect and might be due to another Jarid2 target, Atf3 (Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar). The failure of Jarid2 deletion to rescue Il22 expression in miR-155-deficient Th17 cells complicates the model that miR-155-mediated regulation of Jarid2 is key to the loss of Il22 expression and suggests that additional, miR-155 targets contribute the regulation of Il22. One candidate is the Il22 repressor c-Maf, which binds the locus in the absence of Jarid2 (Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar). One of the major challenges in understanding the action of transcriptional regulators is how they are recruited to specific genes. This is especially critical when regulation is dose-dependent, as described for Jarid2 in miR-155-deficient Th17 cells. Escobar et al., 2014Escobar T.M. Kanellopoulou C. Kugler D.G. Kilaru G. Nguyen C.K. Nagarajan V. Bhairavabhotla R.K. Northrup D. Zahr R. Burr P. et al.Immunity. 2014; 40 (this issue): 865-879Google Scholar show that Il22 and other genes important for Th17 cells, including Il9, Il10, Eomes, Tbx21, and Atf3, are targeted by Jarid2 even in control Th17 cells and that binding merely increased with elevated Jarid2 dosage when miR-155 is deleted. Interestingly, Il22, Il9, and Il10 expression were increased in Jarid2-deficient Th17 cells (Figure 1). The expression of other PRC2 target genes was unaffected, suggesting additional layers of regulation. The impact of Jarid2 on the activity of PRC2 might depend on developmental state: Jarid2 is required not for the self-renewal but for the differentiation of ESCs, even though Jarid2 itself is downregulated during differentiation (Landeira and Fisher, 2011Landeira D. Fisher A.G. Trends Cell Biol. 2011; 21: 74-80https://doi.org/10.1016/j.tcb.2010.10.004Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Is there a similar role for Jarid2 in poising genes for future expression during Th cell differentiation? Finally, miR-155 expression is highly dynamic during T cell activation, and it would be interesting to know how this affects the regulation of miR-155 targets to facilitate changes in the transcriptional and chromatin landscape of activated T cells. The finding that microRNAs and chromatin modifiers form regulatory circuits to control cytokine gene expression is exciting and, in the longer term, might offer opportunities for therapeutic intervention. Th17 cells are important mediators of inflammation and both microRNAs and chromatin modifiers are potential drug targets. miR-155 Activates Cytokine Gene Expression in Th17 Cells by Regulating the DNA-Binding Protein Jarid2 to Relieve Polycomb-Mediated RepressionEscobar et al.ImmunityMay 22, 2014In BriefmiR-155 is known to promote inflammatory Th17 cell responses, but the mechanism has been unclear. Escobar et al. find that miR-155 promotes cytokine expression in Th17 cells by repressing Jarid2 to relieve Polycomb-mediated gene silencing. Full-Text PDF Open Archive
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