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

Nature Structural & Molecular Biology volume 16, pages 1074–1079 (2009)Cite this article

Abstract

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.

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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.

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Acknowledgements

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”.

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  1. Marcus Buschbeck & Lluís Morey

    Present address: Present addresses: Institute for Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain (M.B.); Centre for Epigenetics and BRIC, University of Copenhagen, Copenhagen, Denmark (L.M.).,

Authors and Affiliations

  1. Centre de Regulació Genòmica (CRG), PRBB, Barcelona, Spain

    Marcus Buschbeck, Iris Uribesalgo, Indra Wibowo, Pau Rué, David Martin, Arantxa Gutierrez, Lluís Morey, Roderic Guigó, Hernán López-Schier & Luciano Di Croce

  2. Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, Terrassa, Spain

    Pau Rué

  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    Luciano Di Croce

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Contributions

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.

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Correspondence to Luciano Di Croce.

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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). https://doi.org/10.1038/nsmb.1665

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