Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter

Abstract

Polycomb chromobox (CBX) proteins regulate gene transcription by maintaining chromatin states, which guide a variety of biological processes. Now, epigenetic regulation of innate immune response is an emerging field. However, the role of CBX proteins in innate immunity remains unclear. We confirmed that the expression of CBX family proteins, especially Cbx2, was decreased in macrophages upon viral infection, and then we investigated the role of Cbx2 in the antiviral immune response. Silencing or knockdown of Cbx2 in macrophages inhibited virus-induced production of IFN-β. Furthermore, heterozygous Cbx2 knockout were susceptible to VSV challenge. Mechanistically, Cbx2 binds to and recruits Jmjd3 to the Ifnb promoter, leading to demethylation of H3K27me3 and increased transcription of IFN-β. Together, our study reveals a nontraditional function of a Cbx protein and adds new insight into the epigenetic regulation of antiviral innate immunity.

Keywords

Cbx2 / Jmjd3 / interferon beta / innate immunity

References

[1] Aranda S, Mas G, Di Croce L (2015) Regulation of gene transcription by Polycomb proteins. Sci Adv 1:e1500737

[2] Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326

[3] Cao X (2016) Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat Rev Immunol 16:35–50

[4] Chen WY, Zhang XY, Liu T, Liu Y, Zhao YS, Pang D (2017) Chromobox homolog 2 protein: a novel biomarker for predicting prognosis and Taxol sensitivity in patients with breast cancer. Oncol Lett 13:1149–1156

[5] Chung CY, Sun Z, Mullokandov G, Bosch A, Qadeer ZA, Cihan E, Rapp Z, Parsons R, Aguirre-Ghiso JA, Farias EF (2016) Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis. Cell Rep 16:472–486

[6] Clermont PL, Crea F, Chiang YT, Lin D, Zhang A, Wang JZ, Parolia A, Wu R, Xue H, Wang Y (2016) Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer. Clin Epigenet 8:16

[7] Di Croce L, Helin K (2013) Transcriptional regulation by Polycomb group proteins. Nat Struct Mol Biol 20:1147–1155

[8] Forzati F, Federico A, Pallante P, Abbate A, Esposito F, Malapelle U, Sepe R, Palma G, Troncone G, Scarfo M (2012) CBX7 is a tumor suppressor in mice and humans. J Clin Investig 122:612–623

[9] Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D (2012) PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes. Mol Cell 45:344–356

[10] Garcia-Sastre A (2017) Ten strategies of interferon evasion by viruses. Cell Host Microbe 22:176–184

[11] Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K (2007) Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci USA 104:18439–18444

[12] Iwasaki A, Pillai PS (2014) Innate immunity to influenza virus infection. Nat Rev Immunol 14:315–328

[13] Jiang M, Zhang S, Yang Z, Lin H, Zhu J, Liu L, Wang W, Liu S, Liu W, Ma Y (2018) Self-recognition of an inducible host lncRNA by RIG-I feedback restricts innate immune response. Cell 173(906–919):e913

[14] Katoh-Fukui Y, Tsuchiya R, Shiroishi T, Nakahara Y, Hashimoto N, Noguchi K, Higashinakagawa T (1998) Male-to-female sex reversal in M33 mutant mice. Nature 393:688–692

[15] Kawaguchi T, Machida S, Kurumizaka H, Tagami H, Nakayama JI (2017) Phosphorylation of CBX2 controls its nucleosome-binding specificity. J Biochem 162:343–355

[16] Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384

[17] Li J, Li Y, Cao Y, Yuan M, Gao Z, Guo X, Zhu F, Wang Y, Xu J (2014a) Polycomb chromobox (Cbx) 7 modulates activationinduced CD4+ T cell apoptosis. Arch Biochem Biophys 564:184–188

[18] Li J, Xu Y, Long XD, Wang W, Jiao HK, Mei Z, Yin QQ, Ma LN, Zhou AW, Wang LS (2014b) Cbx4 governs HIF-1alpha to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity. Cancer Cell 25:118–131

[19] Li X, Zhang Q, Ding Y, Liu Y, Zhao D, Zhao K, Shen Q, Liu X, Zhu X, Li N (2016) Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat Immunol 17:806–815

[20] Marcos-Villar L, Diaz-Colunga J, Sandoval J, Zamarreno N, Landeras-Bueno S, Esteller M, Falcon A, Nieto A (2018) Epigenetic control of influenza virus: role of H3K79 methylation in interferon-induced antiviral response. Sci Rep 8:1230

[21] McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A (2015) Type I interferons in infectious disease. Nat Rev Immunol 15:87–103

[22] Santanach A, Blanco E, Jiang H, Molloy KR, Sanso M, LaCava J, Morey L, Di Croce L (2017) The Polycomb group protein CBX6 is an essential regulator of embryonic stem cell identity. Nat Commun 8:1235

[23] Simon JA, Kingston RE (2013) Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put. Mol Cell 49:808–824

[24] Sparmann A, van Lohuizen M (2006) Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6:846–856

[25] Wang C, Wang Q, Xu X, Xie B, Zhao Y, Li N, Cao X (2017) The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3. J Exp Med 214:3597–3610

[26] Wang X, Li L, Wu Y, Zhang R, Zhang M, Liao D, Wang G, Qin G, Xu RH, Kang T (2016) CBX4 suppresses metastasis via recruitment of HDAC3 to the Runx2 promoter in colorectal carcinoma. Cancer Res 76:7277–7289

[27] Wu J, Chen ZJ (2014) Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol 32:461–488

[28] Yoshida K, Maekawa T, Zhu Y, Renard-Guillet C, Chatton B, Inoue K, Uchiyama T, Ishibashi K, Yamada T, Ohno N (2015) The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory. Nat Immunol 16:1034–1043

[29] Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, Zhao D, Liu Y, Wang C, Zhang X (2015) Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525:389–393

[30] Zhang XW, Zhang L, Qin W, Yao XH, Zheng LZ, Liu X, Li J, Guo WJ (2010) Oncogenic role of the chromobox protein CBX7 in gastric cancer. J Exp Clin Cancer Res 29:114

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The Author(s) 2018