Skip to main content

Thank you for visiting 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.

The histone variant macroH2A is an epigenetic regulator of key developmental genes


The histone variants macroH2A1 and macroH2A2 are associated with X chromosome inactivation in female mammals. However, the physiological function of macroH2A proteins on autosomes is poorly understood. Microarray-based analysis in human male pluripotent cells uncovered occupancy of both macroH2A variants at many genes encoding key regulators of development and cell fate decisions. On these genes, the presence of macroH2A1+2 is a repressive mark that overlaps locally and functionally with Polycomb repressive complex 2. We demonstrate that macroH2A1+2 contribute to the fine-tuning of temporal activation of HOXA cluster genes during neuronal differentiation. Furthermore, elimination of macroH2A2 function in zebrafish embryos produced severe but specific phenotypes. Taken together, our data demonstrate that macroH2A variants constitute an important epigenetic mark involved in the concerted regulation of gene expression programs during cellular differentiation and vertebrate development.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



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

Figure 1: Identification of macroH2A target genes by ChIP-on-chip analysis.
Figure 2: Repressive macroH2A targets key developmental genes.
Figure 3: Occupancy by macroH2A inversely correlates with HOXA cluster activation.
Figure 4: Functional overlap of macroH2A and PRC2.
Figure 5: MacroH2A is essential for normal zebrafish embryogenesis.

Accession codes


Gene Expression Omnibus


  1. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  Google Scholar 

  2. Wolffe, A.P. & Matzke, M.A. Epigenetics: regulation through repression. Science 286, 481–486 (1999).

    Article  CAS  Google Scholar 

  3. Sarma, K. & Reinberg, D. Histone variants meet their match. Nat. Rev. Mol. Cell Biol. 6, 139–149 (2005).

    Article  CAS  Google Scholar 

  4. Chakravarthy, S. et al. Structural characterization of the histone variant macroH2A. Mol. Cell. Biol. 25, 7616–7624 (2005).

    Article  CAS  Google Scholar 

  5. Costanzi, C. & Pehrson, J.R. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature 393, 599–601 (1998).

    Article  CAS  Google Scholar 

  6. Angelov, D. et al. The histone variant macroH2A interferes with transcription factor binding and SWI/SNF nucleosome remodeling. Mol. Cell 11, 1033–1041 (2003).

    Article  CAS  Google Scholar 

  7. Doyen, C.M. et al. Mechanism of polymerase II transcription repression by the histone variant macroH2A. Mol. Cell. Biol. 26, 1156–1164 (2006).

    Article  CAS  Google Scholar 

  8. Agelopoulos, M. & Thanos, D. Epigenetic determination of a cell-specific gene expression program by ATF-2 and the histone variant macroH2A. EMBO J. 25, 4843–4853 (2006).

    Article  CAS  Google Scholar 

  9. Ouararhni, K. et al. The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity. Genes Dev. 20, 3324–3336 (2006).

    Article  CAS  Google Scholar 

  10. Nusinow, D.A. et al. Poly(ADP-ribose) polymerase 1 is inhibited by a histone H2A variant, MacroH2A, and contributes to silencing of the inactive X chromosome. J. Biol. Chem. 282, 12851–12859 (2007).

    Article  CAS  Google Scholar 

  11. Karras, G.I. et al. The macro domain is an ADP-ribose binding module. EMBO J. 24, 1911–1920 (2005).

    Article  CAS  Google Scholar 

  12. Kustatscher, G., Hothorn, M., Pugieux, C., Scheffzek, K. & Ladurner, A.G. Splicing regulates NAD metabolite binding to histone macroH2A. Nat. Struct. Mol. Biol. 12, 624–625 (2005).

    Article  CAS  Google Scholar 

  13. Changolkar, L.N. & Pehrson, J.R. macroH2A1 histone variants are depleted on active genes but concentrated on the inactive X chromosome. Mol. Cell. Biol. 26, 4410–4420 (2006).

    Article  CAS  Google Scholar 

  14. Eklund, E.A. The role of HOX genes in malignant myeloid disease. Curr. Opin. Hematol. 14, 85–89 (2007).

    Article  CAS  Google Scholar 

  15. Houldsworth, J., Heath, S.C., Bosl, G.J., Studer, L. & Chaganti, R.S. Expression profiling of lineage differentiation in pluripotential human embryonal carcinoma cells. Cell Growth Differ. 13, 257–264 (2002).

    CAS  PubMed  Google Scholar 

  16. Jørgensen, H.F. et al. Stem cells primed for action: Polycomb repressive complexes restrain the expression of lineage-specific regulators in embryonic stem cells. Cell Cycle 5, 1411–1414 (2006).

    Article  Google Scholar 

  17. Squazzo, S.L. et al. SUZ12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res. 16, 890–900 (2006).

    Article  CAS  Google Scholar 

  18. Boyer, L.A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).

    Article  CAS  Google Scholar 

  19. Lee, T.I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).

    Article  CAS  Google Scholar 

  20. Bracken, A.P., Dietrich, N., Pasini, D., Hansen, K.H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123–1136 (2006).

    Article  CAS  Google Scholar 

  21. Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 16, 2893–2905 (2002).

    Article  CAS  Google Scholar 

  22. Kirmizis, A. et al. Silencing of human Polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 18, 1592–1605 (2004).

    Article  CAS  Google Scholar 

  23. Leucht, C. et al. MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary. Nat. Neurosci. 11, 641–648 (2008).

    Article  CAS  Google Scholar 

  24. Changolkar, L.N. et al. Developmental changes in histone macroH2A1-mediated gene regulation. Mol. Cell. Biol. 27, 2758–2764 (2007).

    Article  CAS  Google Scholar 

  25. Tagami, H., Ray-Gallet, D., Almouzni, G. & Nakatani, Y. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116, 51–61 (2004).

    Article  CAS  Google Scholar 

  26. Vicent, G.P. et al. DNA instructed displacement of histones H2A and H2B at an inducible promoter. Mol. Cell 16, 439–452 (2004).

    Article  CAS  Google Scholar 

  27. Pasini, D., Bracken, A.P., Jensen, M.R., Lazzerini Denchi, E. & Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23, 4061–4071 (2004).

    Article  CAS  Google Scholar 

  28. Buschbeck, M., Hofbauer, S., Croce, L.D., Keri, G. & Ullrich, A. Abl-kinase-sensitive levels of ERK5 and its intrinsic basal activity contribute to leukaemia cell survival. EMBO Rep. 6, 63–69 (2005).

    Article  CAS  Google Scholar 

  29. Villa, R. et al. The methyl-CpG binding protein MBD1 is required for PML-RARα function. Proc. Natl. Acad. Sci. USA 103, 1400–1405 (2006).

    Article  CAS  Google Scholar 

  30. Frank, S.R., Schroeder, M., Fernandez, P., Taubert, S. & Amati, B. Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation. Genes Dev. 15, 2069–2082 (2001).

    Article  CAS  Google Scholar 

  31. O'Geen, H., Nicolet, C.M., Blahnik, K., Green, R. & Farnham, P.J. Comparison of sample preparation methods for ChIP-chip assays. Biotechniques 41, 577–580 (2006).

    Article  CAS  Google Scholar 

  32. Métivier, R. et al. Estrogen receptor-α directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115, 751–763 (2003).

    Article  Google Scholar 

  33. Smyth, G.K. Limma: linear models for microarray data. in Bioinformatics and Computational Biology Solutions Using R and Bioconductor (Springer, New York, 2005).

    Google Scholar 

  34. Ritchie, M.E. et al. A comparison of background correction methods for two-colour microarrays. Bioinformatics 23, 2700–2707 (2007).

    Article  CAS  Google Scholar 

  35. Breitling, R., Armengaud, P., Amtmann, A. & Herzyk, P. Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments. FEBS Lett. 573, 83–92 (2004).

    Article  CAS  Google Scholar 

  36. Hong, F. et al. RankProd: a bioconductor package for detecting differentially expressed genes in meta-analysis. Bioinformatics 22, 2825–2827 (2006).

    Article  CAS  Google Scholar 

  37. Hosack, D.A., Dennis, G., Jr., Sherman, B.T., Lane, H.C. & Lempicki, R.A. Identifying biological themes within lists of genes with EASE. Genome Biol. 4, R70 (2003).

    Article  Google Scholar 

  38. Dennis, G. Jr. et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol. 4, 3 (2003).

    Article  Google Scholar 

  39. Kimmel, C.B., Ballard, W.W., Kimmel, S.R., Ullmann, B. & Schilling, T.F. Stages of embryonic development of the zebrafish. Dev. Dyn. 203, 253–310 (1995).

    Article  CAS  Google Scholar 

  40. Thisse, C. & Thisse, B. High-resolution in situ hybridization to whole-mount zebrafish embryos. Nat. Protoc. 3, 59–69 (2008).

    Article  CAS  Google Scholar 

Download references


We are indebted to T. Rasmussen, G. Dreyfuss (Howard Hughes Medical Institute) for the hnRNP U 4G5 antibody, S. Dimitrov and C. Pujades for reagents and members of the Di Croce laboratory for helpful discussions. This work was supported by grants from the Spanish “Ministerio de Educación y Ciencia” and from “La Marató TV3” and Consolider. M.B. was supported by a Fellowship from Deutsche Forschungsgesellschaft (DFG) and I.U. by a predoctoral fellowship from Spanish “Ministerio de Educación y Ciencia”.

Author information

Authors and Affiliations



M.B., I.U., I.W., A.G. and L.M. performed the experiments; M.B., P.R., D.M., R.G., H.L.-S. and L.D.C. analyzed the data; M.B. and L.D.C. designed the project and wrote the manuscript.

Corresponding author

Correspondence to Luciano Di Croce.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1–3 (PDF 4174 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Buschbeck, M., Uribesalgo, I., Wibowo, I. et al. The histone variant macroH2A is an epigenetic regulator of key developmental genes. Nat Struct Mol Biol 16, 1074–1079 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing