Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Monocyte polarization: the relationship of genome-wide changes in H4 acetylation with polarization

Genes & Immunity volume 12, pages 445–456 (2011)Cite this article

Subjects

Abstract

The character of monocytes is both molded by and contributes to ongoing immune responses. We hypothesized that monocyte polarization could have durable qualities and these would be mediated partly by changes in the chromatin. We defined genome-wide expression and histone H4 acetylation (H4ac) changes after γ-interferon (IFN), α-IFN and interleukin-4 treatment. To identify genes with altered potential for expression, we stimulated polarized monocytes and identified genes up- or downregulated after polarization and stimulation but not either treatment alone. We also defined durability after an 18-h or 3-day washout. Genes uniquely regulated after the combination of polarization and stimulus were durably altered, with 51% of the effects being durable. This gene set was highly enriched for cytokine-induced alterations in H4ac, with P-values ranging from 10−24 to 10−37. Certain regulons defined by patterns of expression were also associated with altered H4ac, with P-values ranging from 10−4 to 10−29. Networking software revealed a high density of mitogen-activated protein (MAP) kinase nodes in these clusters. Therefore, some changes in monocyte gene expression were sustained over a 3-day period. These durably altered gene sets were enriched for changes in H4ac and were associated with potential MAP kinase effects.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM . M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000; 164: 6166–6173.

    Article  CAS  PubMed  Google Scholar 

  2. Mehta A, Brewington R, Chatterji M, Zoubine M, Kinasewitz GT, Peer GT et al. Infection-induced modulation of m1 and m2 phenotypes in circulating monocytes: role in immune monitoring and early prognosis of sepsis. Shock 2004; 22: 423–430.

    Article  CAS  PubMed  Google Scholar 

  3. Sinha P, Clements VK, Ostrand-Rosenberg S . Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol 2005; 174: 636–645.

    Article  CAS  PubMed  Google Scholar 

  4. Hamilton JA, Tak PP . The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases. Arthritis Rheum 2009; 60: 1210–1221.

    Article  PubMed  Google Scholar 

  5. Schiffer L, Bethunaickan R, Ramanujam M, Huang W, Schiffer M, Tao H et al. Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol 2008; 180: 1938–1947.

    Article  CAS  PubMed  Google Scholar 

  6. Weber MS, Prod’homme T, Youssef S, Dunn SE, Rundle CD, Lee L et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med 2007; 13: 935–943.

    Article  CAS  PubMed  Google Scholar 

  7. Watkins SK, Egilmez NK, Suttles J, Stout RD . IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol 2007; 178: 1357–1362.

    Article  CAS  PubMed  Google Scholar 

  8. Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 2005; 115: 2363–2372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ninomiya K, Takahashi A, Fujioka Y, Ishikawa Y, Yokoyama M . Transforming growth factor-beta signaling enhances transdifferentiation of macrophages into smooth muscle-like cells. Hypertens Res 2006; 29: 269–276.

    Article  CAS  PubMed  Google Scholar 

  10. Mylonas KJ, Nair MG, Prieto-Lafuente L, Paape D, Allen JE . Alternatively activated macrophages elicited by helminth infection can be reprogrammed to enable microbial killing. J Immunol 2009; 182: 3084–3094.

    Article  CAS  PubMed  Google Scholar 

  11. Biswas SK, Sica A, Lewis CE . Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol 2008; 180: 2011–2017.

    Article  CAS  PubMed  Google Scholar 

  12. Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP . Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 2005; 65: 3437–3446.

    Article  CAS  PubMed  Google Scholar 

  13. Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J . Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol 2005; 175: 342–349.

    Article  CAS  PubMed  Google Scholar 

  14. Stout RD, Suttles J . Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol 2004; 76: 509–513.

    Article  CAS  PubMed  Google Scholar 

  15. Mantovani A, Sica A, Locati M . Macrophage polarization comes of age. Immunity 2005; 23: 344–346.

    Article  CAS  PubMed  Google Scholar 

  16. Goerdt S, Politz O, Schledzewski K, Birk R, Gratchev A, Guillot P et al. Alternative versus classical activation of macrophages. Pathobiology 1999; 67: 222–226.

    Article  CAS  PubMed  Google Scholar 

  17. Edwards JP, Zhang X, Frauwirth KA, Mosser DM . Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 2006; 80: 1298–1307.

    Article  CAS  PubMed  Google Scholar 

  18. Baetselier PD, Namangala B, Noel W, Brys L, Pays E, Beschin A . Alternative versus classical macrophage activation during experimental African trypanosomosis. Int J Parasitol 2001; 31: 575–587.

    Article  CAS  PubMed  Google Scholar 

  19. Raes G, Van den Bergh R, De Baetselier P, Ghassabeh GH, Scotton C, Locati M et al. Arginase-1 and Ym1 are markers for murine, but not human, alternatively activated myeloid cells. J Immunol 2005; 174: 6561–6562.

    Article  CAS  PubMed  Google Scholar 

  20. Martinez FO, Gordon S, Locati M, Mantovani A . Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol 2006; 177: 7303–7311.

    Article  CAS  PubMed  Google Scholar 

  21. Lumeng CN, Bodzin JL, Saltiel AR . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117: 175–184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 2006; 107: 2112–2122.

    Article  CAS  PubMed  Google Scholar 

  23. Ghassabeh GH, De Baetselier P, Brys L, Noel W, Van Ginderachter JA, Meerschaut S et al. Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. Blood 2006; 108: 575–583.

    Article  CAS  PubMed  Google Scholar 

  24. Bird A . DNA methylation patterns and epigenetic memory. Genes Dev 2002; 16: 6–21.

    Article  CAS  PubMed  Google Scholar 

  25. Reik W . Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 2007; 447: 425–432.

    Article  CAS  PubMed  Google Scholar 

  26. Jones PA, Baylin SB . The epigenomics of cancer. Cell 2007; 128: 683–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 2010; 11: 936–944.

    Article  CAS  PubMed  Google Scholar 

  28. Ishii M, Wen H, Corsa CA, Liu T, Coelho AL, Allen RM et al. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 2009; 114: 3244–3254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Agalioti T, Chen G, Thanos D . Deciphering the transcriptional histone acetylation code for a human gene. Cell 2002; 111: 381–392.

    Article  CAS  PubMed  Google Scholar 

  30. Schubeler D, MacAlpine DM, Scalzo D, Wirbelauer C, Kooperberg C, van Leeuwen F et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev 2004; 18: 1263–1271.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Garrett S, Dietzmann-Maurer K, Song L, Sullivan KE . Polarization of primary human monocytes by IFN-gamma induces chromatin changes and recruits RNA Pol II to the TNF-alpha promoter. J Immunol 2008; 180: 5257–5266.

    Article  CAS  PubMed  Google Scholar 

  32. Sullivan KE, Reddy AB, Dietzmann K, Suriano AR, Kocieda VP, Stewart M et al. Epigenetic regulation of tumor necrosis factor alpha. Mol Cell Biol 2007; 27: 5147–5160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Strauss-Ayali D, Conrad SM, Mosser DM . Monocyte subpopulations and their differentiation patterns during infection. J Leukoc Biol 2007; 82: 244–252.

    Article  CAS  PubMed  Google Scholar 

  34. Gordon S . Alternative activation of macrophages. Nat Rev Immunol 2003; 3: 23–35.

    Article  CAS  PubMed  Google Scholar 

  35. Munder M, Eichmann K, Moran JM, Centeno F, Soler G, Modolell M . Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J Immunol 1999; 163: 3771–3777.

    CAS  PubMed  Google Scholar 

  36. Raes G, De Baetselier P, Noel W, Beschin A, Brombacher F, Hassanzadeh Gh G . Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol 2002; 71: 597–602.

    CAS  PubMed  Google Scholar 

  37. Welch JS, Escoubet-Lozach L, Sykes DB, Liddiard K, Greaves DR, Glass CK . TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J Biol Chem 2002; 277: 42821–42829.

    Article  CAS  PubMed  Google Scholar 

  38. Martinez FO, Gordon S, Locati M, Mantovani A . Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol 2006; 177: 7303–7311.

    Article  CAS  PubMed  Google Scholar 

  39. Then Bergh F, Dayyani F, Ziegler-Heitbrock L . Impact of type-I-interferon on monocyte subsets and their differentiation to dendritic cells. An in vivo and ex vivo study in multiple sclerosis patients treated with interferon-beta. J Neuroimmunol 2004; 146: 176–188.

    Article  CAS  PubMed  Google Scholar 

  40. Cros J, Cagnard N, Woollard K, Patey N, Zhang SY, Senechal B et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 2010; 33: 375–386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Clayton AL, Hazzalin CA, Mahadevan LC . Enhanced histone acetylation and transcription: a dynamic perspective. Mol Cell 2006; 23: 289–296.

    Article  CAS  PubMed  Google Scholar 

  42. Sullivan KE, Jawad AF, Piliero LM, Kim N, Luan X, Goldman D et al. Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus. Rheumatology 2003; 42: 446–452.

    Article  CAS  PubMed  Google Scholar 

  43. Barrionuevo P, Beigier-Bompadre M, Fernandez GC, Gomez S, Alves-Rosa MF, Palermo MS et al. Immune complex-FcgammaR interaction modulates monocyte/macrophage molecules involved in inflammation and immune response. Clin Exp Immunol 2003; 133: 200–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gehani SS, Agrawal-Singh S, Dietrich N, Christophersen NS, Helin K, Hansen K . Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation. Mol Cell 2010; 39: 886–900.

    Article  CAS  PubMed  Google Scholar 

  45. Suganuma T, Mushegian A, Swanson SK, Abmayr SM, Florens L, Washburn MP et al. The ATAC acetyltransferase complex coordinates MAP kinases to regulate JNK target genes. Cell 2010; 142: 726–736.

    Article  CAS  PubMed  Google Scholar 

  46. Drobic B, Perez-Cadahia B, Yu J, Kung SK, Davie JR . Promoter chromatin remodeling of immediate-early genes is mediated through H3 phosphorylation at either serine 28 or 10 by the MSK1 multi-protein complex. Nucleic Acids Res 2010; 38: 3196–3208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 2007; 39: 311–318.

    Article  CAS  PubMed  Google Scholar 

  48. Edmunds JW, Mahadevan LC . MAP kinases as structural adaptors and enzymatic activators in transcription complexes. J Cell Sci 2004; 117 (Part 17): 3715–3723.

    Article  CAS  PubMed  Google Scholar 

  49. Thomson S, Mahadevan LC, Clayton AL . MAP kinase-mediated signalling to nucleosomes and immediate-early gene induction. Semin Cell Dev Biol 1999; 10: 205–214.

    Article  CAS  PubMed  Google Scholar 

  50. Nowak SJ, Corces VG . Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation. Trends Genet 2004; 20: 214–220.

    Article  CAS  PubMed  Google Scholar 

  51. Strelkov IS, Davie JR . Ser-10 phosphorylation of histone H3 and immediate early gene expression in oncogene-transformed mouse fibroblasts. Cancer Res 2002; 62: 75–78.

    CAS  PubMed  Google Scholar 

  52. Thomson S, Clayton AL, Mahadevan LC . Independent dynamic regulation of histone phosphorylation and acetylation during immediate-early gene induction. Mol Cell 2001; 8: 1231–1241.

    Article  CAS  PubMed  Google Scholar 

  53. Xiao S, Xu C, Jarvis JN . C1q-bearing immune complexes induce IL-8 secretion in human umbilical vein endothelial cells (HUVEC) through protein tyrosine kinase- and mitogen-activated protein kinase-dependent mechanisms: evidence that the 126 kD phagocytic C1q receptor mediates immune complex activation of HUVEC. Clin Exp Immunol 2001; 125: 360–367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Belge KU, Dayyani F, Horelt A, Siedlar M, Frankenberger M, Frankenberger B et al. The proinflammatory CD14(+)CD16(+) DR(++) monocytes are a major source of TNF. J Immunol 2002; 168: 3536–3542.

    Article  CAS  PubMed  Google Scholar 

  55. Johnson WE, Li W, Meyer CA, Gottardo R, Carroll JS, Brown M et al. Model-based analysis of tiling-arrays for ChIP-chip. Proc Natl Acad Sci USA 2006; 103: 12457–12462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ji H, Jiang H, Ma W, Johnson DS, Myers RM, Wong WH . An integrated software system for analyzing ChIP-chip and ChIP-seq data. Nat Biotechnol 2008; 26: 1293–1300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP . Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 2003; 31: e15.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Dai M, Wang P, Boyd AD, Kostov G, Athey B, Jones EG et al. Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res 2005; 33: e175.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported, in part, by NIH R01 AI 0511323 and R01 ES 017627.

Author information

Authors and Affiliations

  1. Center for Bioinformatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    Z Zhang

  2. Division of Allergy Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    L Song, K Maurer, A Bagashev & K E Sullivan

Authors
  1. Z Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Maurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Bagashev
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K E Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K E Sullivan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Z., Song, L., Maurer, K. et al. Monocyte polarization: the relationship of genome-wide changes in H4 acetylation with polarization. Genes Immun 12, 445–456 (2011). https://doi.org/10.1038/gene.2011.17

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2011.17

Keywords

This article is cited by

Search

Advanced search

Quick links