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A unique H2A histone variant occupies the transcriptional start site of active genes

Nature Structural & Molecular Biology volume 19, pages 25–30 (2012)Cite this article

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Abstract

Transcriptional activation is controlled by chromatin, which needs to be unfolded and remodeled to ensure access to the transcription start site (TSS). However, the mechanisms that yield such an 'open' chromatin structure, and how these processes are coordinately regulated during differentiation, are poorly understood. We identify the mouse (Mus musculus) H2A histone variant H2A.Lap1 as a previously undescribed component of the TSS of active genes expressed during specific stages of spermatogenesis. This unique chromatin landscape also includes a second histone variant, H2A.Z. In the later stages of round spermatid development, H2A.Lap1 dynamically loads onto the inactive X chromosome, enabling the transcriptional activation of previously repressed genes. Mechanistically, we show that H2A.Lap1 imparts unique unfolding properties to chromatin. We therefore propose that H2A.Lap1 coordinately regulates gene expression by directly opening the chromatin structure of the TSS at genes regulated during spermatogenesis.

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Figure 1: H2A.Lap1 dynamically loads onto the sex chromosomes in late round spermatids.
Figure 2: H2A.Lap1 is located at the TSS of active genes.
Figure 3: Targeting of H2A.Lap1 to X chromosome–linked genes occurs in late round spermatids.
Figure 4: H2A.Lap1 has gained a single acidic amino acid residue, which enables nucleosome arrays to partially fold.

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Change history

  • 11 December 2011

    In the version of this article initially published, the incorrect PDB code for the MthK open channel structure was provided in the legend to Figure 1. The correct PDB code for this structure is 1LNQ. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank J. Fan (The Australian National University) for initial protein preparations of H2A.Lap1, J. Pehrson (University of Pennsylvania) for macroH2A antibodies, K. Luger (Colorado State University) for core histone recombinant proteins, S. McBryant and J. Hansen for helping M.N. to set up sedimentation velocity experiments, S. Grigoryev and R. Reeves for reading the manuscript, our in-house Biomolecular Research Service, headed by S. Palmer, for high-throughput DNA sequencing, and A. Prins and C. Gillespie for help in histological sample preparation and microscopy. This work was supported by Australian National Health and Medical Research Council project grants to T.A.S. and D.J.T., and to M.N. and D.J.T.

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  1. Rohan Williams

    Present address: Present address: Singapore Centre on Environmental Life Sciences Engineering, National University of Singapore, Singapore.,

Authors and Affiliations

  1. The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.,

    Tatiana A Soboleva, Maxim Nekrasov, Anuj Pahwa, Rohan Williams, Gavin A Huttley & David J Tremethick

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Contributions

T.A.S. helped design the experiments, cloned H2A.Lap, conducted all spermatogenesis experiments, prepared chromatin for ChIP-seq experiments and conducted the gene expression and ChIP experiments on individual X-chromosome genes. M.N. conducted the biochemical and biophysical experiments on the nucleosome arrays and prepared DNA ChIP libraries for high-throughput sequencing. R.W. developed and did data analysis of global mouse gene expression data. G.A.H. designed and executed the analysis of the Illumina short-read data. A.P. assisted with the analyses of Illumina short-read data. D.J.T. conceived the project, helped design the experiments and wrote the manuscript.

Corresponding author

Correspondence to David J Tremethick.

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The authors declare no competing financial interests.

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Supplementary Figures 1–8, Supplementary Table 1 and Supplementary Methods (PDF 2300 kb)

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Soboleva, T., Nekrasov, M., Pahwa, A. et al. A unique H2A histone variant occupies the transcriptional start site of active genes. Nat Struct Mol Biol 19, 25–30 (2012). https://doi.org/10.1038/nsmb.2161

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