The chemokine receptor CCR5 regulates trafficking of immune cells of the lymphoid and the myeloid lineage (such as monocytes, macrophages and immature dendritic cells) and microglia. Because of this, there is an increasing recognition of the important role of CCR5 in the pathology of (neuro-) inflammatory diseases such as atherosclerosis and multiple sclerosis. Expression of CCR5 is under the control of a complexly organized promoter region upstream of the gene. The transcription factor cAMP-responsive element binding protein 1 (CREB-1) transactivates the CCR5 P1 promoter. The cell-specific expression of CCR5 however is realized by using various epigenetic marks providing a multivalent chromatin state particularly in monocytes. Here we discuss the transcriptional regulation of CCR5 with a focus on the epigenetic peculiarities of CCR5 transcription.
References
[1]
Samson, M.; Labbe, O.; Mollereau, C.; Vassart, G.; Parmentier, M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 1996, 35, 3362–3367, doi:10.1021/bi952950g.
[2]
Combadiere, C.; Ahuja, S.K.; Tiffany, H.L.; Murphy, P.M. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTS. J. Leukoc. Biol. 1996, 60, 147–152.
[3]
Raport, C.J.; Gosling, J.; Schweickart, V.L.; Gray, P.W.; Charo, I.F. Molecular cloning and functional characterization of a novel human CC chemokine receptor (CCR5) for RANTES, MIP-1beta, and MIP-1alpha. J. Biol. Chem. 1996, 271, 17161–17166.
[4]
Bursill, C.A.; Channon, K.M.; Greaves, D.R. The role of chemokines in atherosclerosis: Recent evidence from experimental models and population genetics. Curr. Opin. Lipidol. 2004, 15, 145–149, doi:10.1097/00041433-200404000-00007.
[5]
Ribeiro, S.; Horuk, R. The clinical potential of chemokine receptor antagonists. Pharmacol. Ther. 2005, 107, 44–58, doi:10.1016/j.pharmthera.2005.01.004.
[6]
Biber, K.; Zuurman, M.W.; Dijkstra, I.M.; Boddeke, H.W. Chemokines in the brain: Neuroimmunology and beyond. Curr. Opin. Pharmacol. 2002, 2, 63–68, doi:10.1016/S1471-4892(01)00122-9.
[7]
Schober, A. Chemokines in vascular dysfunction and remodeling. Arterioscler. Thromb. Vasc. Biol. 2008, 28, 1950–1959, doi:10.1161/ATVBAHA.107.161224.
[8]
Zernecke, A.; Liehn, E.A.; Gao, J.-L.; Kuziel, W.A.; Murphy, P.M.; Weber, C. Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: Involvement of IL-10. Blood 2006, 107, 4240–4243, doi:10.1182/blood-2005-09-3922.
[9]
Zernecke, A.; Shagdarsuren, E.; Weber, C. Chemokines in atherosclerosis: An update. Arterioscler. Thromb. Vasc. Biol. 2008, 28, 1897–1908, doi:10.1161/ATVBAHA.107.161174.
[10]
Kraaijeveld, A.O.; de Jager, S.C.; de Jager, W.J.; Prakken, B.J.; McColl, S.R.; Haspels, I.; Putter, H.; van Berkel, T.J.; Nagelkerken, L.; Jukema, J.W.; et al. CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischemic symptoms. Circulation 2007, 116, 1931–1941, doi:10.1161/CIRCULATIONAHA.107.706986.
[11]
Wu, L.; Paxton, W.A.; Kassam, N.; Ruffing, N.; Rottman, J.B.; Sullivan, N.; Choe, H.; Sodroski, J.; Newman, W.; Koup, R.A.; et al. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro. J. Exp. Med. 1997, 185, 1681–1691, doi:10.1084/jem.185.9.1681.
[12]
Oswald-Richter, K.; Grill, S.M.; Leelawong, M.; Tseng, M.; Kalams, S.A.; Hulgan, T.; Haas, D.W.; Unutmaz, D. Identification of a CCR5-expressing T cell subset that is resistant to R5-tropic HIV infection. PLoS Pathog. 2007, 3, e58, doi:10.1371/journal.ppat.0030058.
[13]
Carrington, M.; Dean, M.; Martin, M.P.; O’Brien, S.J. Genetics of HIV-1 infection: Chemokine receptor CCR5 polymorphism and its consequences. Hum. Mol. Genet. 1999, 8, 1939–1945.
[14]
Ebert, L.M.; McColl, S.R. Up-regulation of CCR5 and CCR6 on distinct subpopulations of antigen-activated CD4+ T lymphocytes. J. Immunol. 2002, 168, 65–72.
[15]
Mummidi, S.; Adams, L.M.; VanCompernolle, S.E.; Kalkonde, M.; Camargo, J.F.; Kulkarni, H.; Bellinger, A.S.; Bonello, G.; Tagoh, H.; Ahuja, S.S.; et al. Production of specific mRNA transcripts, usage of an alternate promoter, and octamer-binding transcription factors influence the surface expression levels of the HIV coreceptor CCR5 on primary T cells. J. Immunol. 2007, 178, 5668–5681.
[16]
Mummidi, S.; Ahuja, S.S.; McDaniel, B.L.; Ahuja, S.K. The human CC chemokine receptor 5 (CCR5) gene. Multiple transcripts with 5'-end heterogeneity, dual promoter usage, and evidence for polymorphisms within the regulatory regions and noncoding exons. J. Biol. Chem. 1997, 272, 30662–30671.
[17]
Bleul, C.C.; Wu, L.; Hoxie, J.A.; Springer, T.A.; Mackay, C.R. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc. Natl. Acad. Sci. USA 1997, 94, 1925–1930, doi:10.1073/pnas.94.5.1925.
[18]
Guignard, F.; Combadiere, C.; Tiffany, H.L.; Murphy, P.M. Gene organization and promoter function for CC chemokine receptor 5 (CCR5). J. Immunol. 1998, 160, 985–992.
[19]
Van der Merwe, P.A.; Davis, S.J. The immunological synapse—A multitasking system. Science 2002, 295, 1479–1480, doi:10.1126/science.1069896.
[20]
Grakoui, A.; Bromley, S.K.; Sumen, C.; Davis, M.M.; Shaw, A.S.; Allen, P.M.; Dustin, M.L. The immunological synapse: A molecular machine controlling T cell activation. Science 1999, 285, 221–227, doi:10.1126/science.285.5425.221.
[21]
Rossi, D.; Zlotnik, A. The biology of chemokines and their receptors. Annu. Rev. Immunol. 2000, 18, 217–242, doi:10.1146/annurev.immunol.18.1.217.
[22]
Serbina, N.V.; Jia, T.; Hohl, T.M.; Pamer, E.G. Monocyte-mediated defense against microbial pathogens. Annu. Rev. Immunol. 2008, 26, 421–452, doi:10.1146/annurev.immunol.26.021607.090326.
[23]
Schmitz, G.; Leuthauser-Jaschinski, K.; Orso, E. Are circulating monocytes as microglia orthologues appropriate biomarker targets for neuronal diseases? Cent. Nerv. Syst. Agents Med. Chem. 2009, 9, 307–330, doi:10.2174/187152409789630424.
[24]
Chan, W.Y.; Kohsaka, S.; Rezaie, P. The origin and cell lineage of microglia: New concepts. Brain Res. Rev. 2007, 53, 344–354, doi:10.1016/j.brainresrev.2006.11.002.
[25]
Hansson, G.K.; Robertson, A.K.L.; Soderberg-Naucler, C. Inflammation and atherosclerosis. Annu. Rev. Pathol. 2006, 1, 297–329, doi:10.1146/annurev.pathol.1.110304.100100.
[26]
Libby, P. Inflammation in atherosclerosis. Nature 2002, 420, 868–874, doi:10.1038/nature01323.
[27]
Noseworthy, J.H.; Lucchinetti, C.; Rodriguez, M.; Weinshenker, B.G. Multiple sclerosis. N. Engl. J. Med. 2000, 343, 938–952, doi:10.1056/NEJM200009283431307.
[28]
Fox, R.J.; Kivisakk, P.; Fisher, E.; Tucky, B.; Lee, J.C.; Rudick, R.A.; Ransohoff, R.M. Multiple sclerosis: Chemokine receptor expression on circulating lymphocytes in correlation with radiographic measures of tissue injury. Mult. Scler. 2008, 14, 1036–1043, doi:10.1177/1352458508092261.
[29]
Trebst, C.; Konig, F.; Ransohoff, R.; Bruck, W.; Stangel, M. CCR5 expression on macrophages/microglia is associated with early remyelination in multiple sclerosis lesions. Mult. Scler. 2008, 14, 728–733, doi:10.1177/1352458508089359.
[30]
Mummidi, S.; Bamshad, M.; Ahuja, S.S.; Gonzalez, E.; Feuillet, P.M.; Begum, K.; Galvis, M.C.; Kostecki, V.; Valente, A.J.; Murthy, K.K.; et al. Evolution of human and non-human primate CC chemokine receptor 5 gene and mRNA. Potential roles for haplotype and mRNA diversity, differential haplotype-specific transcriptional activity, and altered transcription factor binding to polymorphic nucleotides in the pathogenesis of HIV-1 and simian immunodeficiency virus. J. Biol. Chem. 2000, 275, 18946–18961.
[31]
Wierda, R.J.; Kuipers, H.F.; van Eggermond, M.C.J.A.; Benard, A.; van Leeuwen, J.C.; Carluccio, S.; Geutskens, S.B.; Jukema, J.W.; Marquez, V.E.; Quax, P.H.A.; et al. Epigenetic control of CCR5 transcript levels in immune cells and modulation by small molecules inhibitors. J. Cell. Mol. Med. 2012, 16, 1866–1877, doi:10.1111/j.1582-4934.2011.01482.x.
[32]
Liu, R.; Zhao, X.; Gurney, T.A.; Landau, N.R. Functional analysis of the proximal CCR5 promoter. AIDS Res. Hum. Retroviruses 1998, 14, 1509–1519, doi:10.1089/aid.1998.14.1509.
[33]
Kuipers, H.F.; Biesta, P.J.; Montagne, L.J.; van Haastert, E.S.; van der Valk, P.; van den Elsen, P.J. CC chemokine receptor 5 gene promoter activation by the cyclic AMP response element binding transcription factor. Blood 2008, 112, 1610–1619, doi:10.1182/blood-2008-01-135111.
[34]
Banerjee, A.; Pirrone, V.; Wigdahl, B.; Nonnemacher, M.R. Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway. Biomed. Pharmacother. 2011, 65, 293–297, doi:10.1016/j.biopha.2011.03.009.
[35]
Jin, Q.; Agrawal, L.; Meyer, L.; Tubiana, R.; Theodorou, I.; Alkhatib, G. CCR5Delta32 59537-G/A promoter polymorphism is associated with low translational efficiency and the loss of CCR5Delta32 protective effects. J. Virol. 2008, 82, 2418–2426, doi:10.1128/JVI.01596-07.
[36]
Moriuchi, H.; Moriuchi, M.; Fauci, A.S. Cloning and analysis of the promoter region of CCR5, a coreceptor for HIV-1 entry. J. Immunol. 1997, 159, 5441–5449.
[37]
Moriuchi, M.; Moriuchi, H. Octamer transcription factors up-regulate the expression of CCR5, a coreceptor for HIV-1 entry. J. Biol. Chem. 2001, 276, 8639–8642.
[38]
Moriuchi, M.; Moriuchi, H. YY1 transcription factor down-regulates expression of CCR5, a major coreceptor for HIV-1. J. Biol. Chem. 2003, 278, 13003–13007, doi:10.1074/jbc.M204980200.
[39]
Moriuchi, M.; Moriuchi, H.; Fauci, A.S. GATA-1 transcription factor transactivates the promoter for CCR5, a coreceptor for human immunodeficiency virus type 1 entry. Blood 1999, 93, 1433–1435.
[40]
Richardson, M.W.; Jadlowsky, J.; Didigu, C.A.; Doms, R.W.; Riley, J.L. Kruppel-like Factor 2 Modulates CCR5 Expression and Susceptibility to HIV-1 Infection. J. Immunol. 2012, doi:10.4049/jimmunol.1201431.
[41]
Jaenisch, R.; Bird, A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat. Genet. 2003, 33, 245–254, doi:10.1038/ng1089.
Takai, D.; Jones, P.A. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc. Natl. Acad. Sci. USA 2002, 99, 3740–3745, doi:10.1073/pnas.052410099.
[44]
Larsen, F.; Gundersen, G.; Lopez, R.; Prydz, H. CpG islands as gene markers in the human genome. Genomics 1992, 13, 1095–1107, doi:10.1016/0888-7543(92)90024-M.
[45]
Kulis, M.; Esteller, M. DNA methylation and cancer. Adv. Genet. 2010, 70, 27–56, doi:10.1016/B978-0-12-380866-0.60002-2.
[46]
Irizarry, R.A.; Ladd-Acosta, C.; Wen, B.; Wu, Z.; Montano, C.; Onyango, P.; Cui, H.; Gabo, K.; Rongione, M.; Webster, M.; et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat. Genet. 2009, 41, 178–186, doi:10.1038/ng.298.
[47]
Rice, J.C.; Briggs, S.D.; Ueberheide, B.; Barber, C.M.; Shabanowitz, J.; Hunt, D.F.; Shinkai, Y.; Allis, C.D. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol. Cell 2003, 12, 1591–1598, doi:10.1016/S1097-2765(03)00479-9.
[48]
Cao, R.; Zhang, Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr. Opin. Genet. Dev. 2004, 14, 155–164, doi:10.1016/j.gde.2004.02.001.
[49]
Schotta, G.; Lachner, M.; Sarma, K.; Ebert, A.; Sengupta, R.; Reuter, G.; Reinberg, D.; Jenuwein, T. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 2004, 18, 1251–1262, doi:10.1101/gad.300704.
[50]
Martin, C.; Zhang, Y. The diverse functions of histone lysine methylation. Nat. Rev. Mol. Cell Biol. 2005, 6, 838–849, doi:10.1038/nrm1761.
[51]
Wang, P.; Lin, C.; Smith, E.R.; Guo, H.; Sanderson, B.W.; Wu, M.; Gogol, M.; Alexander, T.; Seidel, C.; Wiedemann, L.M.; et al. Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol. Cell. Biol. 2009, 29, 6074–6085.
[52]
Yan, C.; Boyd, D.D. Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression. Mol. Cell. Biol. 2006, 26, 6357–6371, doi:10.1128/MCB.00311-06.
[53]
Strahl, B.D.; Allis, C.D. The language of covalent histone modifications. Nature 2000, 403, 41–45, doi:10.1038/47412.
[54]
Vaissiere, T.; Sawan, C.; Herceg, Z. Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat. Res. 2008, 659, 40–48, doi:10.1016/j.mrrev.2008.02.004.
[55]
Lamond, A.I.; Earnshaw, W.C. Structure and function in the nucleus. Science 1998, 280, 547–553, doi:10.1126/science.280.5363.547.
[56]
Van Steensel, B. Chromatin: Constructing the big picture. EMBO J. 2011, 30, 1885–1895, doi:10.1038/emboj.2011.135.
[57]
Schwartz, Y.B.; Pirrotta, V. Polycomb complexes and epigenetic states. Curr. Opin. Cell Biol. 2008, 20, 266–273, doi:10.1016/j.ceb.2008.03.002.
Ball, D.J.; Gross, D.S.; Garrard, W.T. 5-methylcytosine is localized in nucleosomes that contain histone H1. Proc. Natl. Acad. Sci. USA 1983, 80, 5490–5494, doi:10.1073/pnas.80.18.5490.
[60]
Bernstein, B.E.; Mikkelsen, T.S.; Xie, X.; Kamal, M.; Huebert, D.J.; Cuff, J.; Fry, B.; Meissner, A.; Wernig, M.; Plath, K.; et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 2006, 125, 315–326, doi:10.1016/j.cell.2006.02.041.
[61]
Bapat, S.A.; Jin, V.; Berry, N.; Balch, C.; Sharma, N.; Kurrey, N.; Zhang, S.; Fang, F.; Lan, X.; Li, M.; et al. Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells. Epigenetics 2010, 5, 716–729, doi:10.4161/epi.5.8.13014.
[62]
De Gobbi, M.; Garrick, D.; Lynch, M.; Vernimmen, D.; Hughes, J.R.; Goardon, N.; Luc, S.; Lower, K.M.; Sloane-Stanley, J.A.; Pina, C.; et al. Generation of bivalent chromatin domains during cell fate decisions. Epigenet. Chromatin 2011, 4, 9, doi:10.1186/1756-8935-4-9.
[63]
Saito, A.; Yamashita, T.; Mariko, Y.; Nosaka, Y.; Tsuchiya, K.; Ando, T.; Suzuki, T.; Tsuruo, T.; Nakanishi, O. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc. Natl. Acad. Sci. USA 1999, 96, 4592–4597.
[64]
Hu, E.; Dul, E.; Sung, C.-M.; Chen, Z.; Kirkpatrick, R.; Zhang, G.-F.; Johanson, K.; Liu, R.; Lago, A.; Hofmann, G.; et al. Identification of novel isoform-selective inhibitors within class I histone deacetylases. J. Pharmacol. Exp. Ther. 2003, 307, 720–728, doi:10.1124/jpet.103.055541.
[65]
Vannini, A.; Volpari, C.; Filocamo, G.; Casavola, E.C.; Brunetti, M.; Renzoni, D.; Chakravarty, P.; Paolini, C.; de Francesco, R.; Gallinari, P.; et al. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc. Natl. Acad. Sci. USA 2004, 101, 15064–15069.
[66]
Matalon, S.; Palmer, B.E.; Nold, M.F.; Furlan, A.; Kassu, A.; Fossati, G.; Mascagni, P.; Dinarello, C.A. The histone deacetylase inhibitor ITF2357 decreases surface CXCR4 and CCR5 expression on CD4(+) T-cells and monocytes and is superior to valproic acid for latent HIV-1 expression in vitro. J. Acquir. Immune Defic. Syndr. 2010, 54, 1–9.
[67]
Gerstner, T.; Bell, N.; Konig, S. Oral valproic acid for epilepsy—Long-term experience in therapy and side effects. Expert. Opin. Pharmacother. 2008, 9, 285–292, doi:10.1517/14656566.9.2.285.
[68]
Henry, T.R. The history of valproate in clinical neuroscience. Psychopharmacol. Bull. 2003, 37, 5–16.