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.

Splicing of Ezh1 gets muscle out of stressful situations

Nature Structural & Molecular Biology volume 24, pages 435–437 (2017)Cite this article

Subjects

As cells undergo terminal differentiation, the composition of Polycomb-repressive complex 2 (PRC2) changes and the histone H3K27 methyltransferase Ezh2 is progressively replaced by its homolog Ezh1. By identifying an enzymatically inactive splice variant of Ezh1 that is sensitive to cellular stress, Bodega et al. now demonstrate that PRC2–Ezh1 has an essential role in establishing an altered gene expression program required for postmitotic muscle cells to adapt to environmental changes.

Polycomb group (PcG) proteins play essential roles in establishing and maintaining spatial and temporal gene expression patterns required for normal development1. Identification of mutations in genes coding for PcG proteins in multiple cancer types suggests that these proteins also play critical roles in maintaining homeostasis of adult tissues2. PcG proteins contribute to cell-specific gene repression via multiple mechanisms. The best characterized of these mechanisms is mediated by the protein complex PRC2, which marks chromatin for condensation via trimethylation of histone H3 at lysine 27 (H3K27me3). PRC2 activity can be mediated by Ezh2 or Ezh1, two histone methyltransferases that are mutually exclusive components of alternate PRC2 complexes3. Shared components of PRC2 complexes include the Suz12 and Eed subunits, which also play an essential role in PRC2-mediated H3K27 methylation4,5. PRC2–Ezh2 is generally considered the major contributor to H3K27me3 regulation during development, because Ezh1-knockout mice are viable6. Ezh1 cannot rescue the embryonic lethality of an Ezh2 knockout7, and deletion of Ezh1 in embryonic stem cells does not result in significant depletion of global H3K27me3 levels8. Recent work in germ cells, however, suggests that PRC2–Ezh1 complexes can compensate for loss of Ezh2 during spermatogenesis, a specialized developmental process in which cells express a high level of Ezh1 (ref. 9). This suggests that the relative amount of functional PRC2–Ezh1 versus PRC2–Ezh2 in the cell might regulate their individual contributions to total H3K27me3-mediated transcriptional repression. Interestingly, during terminal muscle differentiation, the repression of Ezh2 expression coincides with an upregulation of Ezh110,11, resulting in an Ezh2-to-Ezh1 switch in PRC2 complexes. However, the role of PRC2–Ezh1 in postmitotic muscle cells remained to be established. In an exciting study, Bodega et al.12 have now shown that PRC2–Ezh1 plays a key role in the adaptation of postmitotic skeletal myofibers to oxidative stress by quickly downregulating the expression of genes involved in muscle function.

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

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Splicing of Ezh1 limits the level of functional PRC2 complex in healthy cells while allowing a rapid adaptive response to oxidative stress.

References

  1. Geisler, S.J. & Paro, R. Development 142, 2876–2887 (2015).

    Article  CAS  Google Scholar 

  2. Pasini, D. & Di Croce, L. Curr. Opin. Genet. Dev. 36, 50–58 (2016).

    Article  CAS  Google Scholar 

  3. Shen, X. et al. Mol. Cell 32, 491–502 (2008).

    Article  CAS  Google Scholar 

  4. Cao, R. & Zhang, Y. Mol. Cell 15, 57–67 (2004).

    Article  CAS  Google Scholar 

  5. Margueron, R. et al. Nature 461, 762–767 (2009).

    Article  CAS  Google Scholar 

  6. Ezhkova, E. et al. Genes Dev. 25, 485–498 (2011).

    Article  CAS  Google Scholar 

  7. O'Carroll, D. et al. Mol. Cell. Biol. 21, 4330–4336 (2001).

    Article  CAS  Google Scholar 

  8. Margueron, R. et al. Mol. Cell 32, 503–518 (2008).

    Article  CAS  Google Scholar 

  9. Mu, W., Starmer, J., Shibata, Y., Yee, D. & Magnuson, T. Dev. Biol. 424, 198–207 (2017).

    Article  CAS  Google Scholar 

  10. Caretti, G., Di Padova, M., Micales, B., Lyons, G.E. & Sartorelli, V. Genes Dev. 18, 2627–2638 (2004).

    Article  CAS  Google Scholar 

  11. Stojic, L. et al. Epigenetics Chromatin 4, 16 (2011).

    Article  CAS  Google Scholar 

  12. Bodega, B. et al. Nat. Struct. Mol. Biol. 24, 444–452 (2017).

    Article  CAS  Google Scholar 

  13. Xu, B. et al. Blood 125, 346–357 (2015).

    Article  CAS  Google Scholar 

  14. Mousavi, K., Zare, H., Wang, A.H. & Sartorelli, V. Mol. Cell 45, 255–262 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Work in the Brand and Dilworth labs is supported by grants from the Canadian Institutes of Health Research (MOP-82813 to M.B. and FDN-143330 to F.J.D.).

Author information

Authors and Affiliations

  1. and the Department of Cellular and Molecular Medicine, Marjorie Brand and F. Jeffrey Dilworth are at the Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, University of Ottawa, Ottawa, Ontario, Canada.,

    Marjorie Brand & F Jeffrey Dilworth

Authors
  1. Marjorie Brand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Jeffrey Dilworth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Marjorie Brand or F Jeffrey Dilworth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brand, M., Dilworth, F. Splicing of Ezh1 gets muscle out of stressful situations. Nat Struct Mol Biol 24, 435–437 (2017). https://doi.org/10.1038/nsmb.3406

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.3406

Search

Advanced search

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