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Histone H3 lysine 9 trimethylation and HP1γ favor inclusion of alternative exons

Nature Structural & Molecular Biology volume 18, pages 337–344 (2011)Cite this article

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Abstract

Pre-messenger RNAs (pre-mRNAs) maturation is initiated cotranscriptionally. It is therefore conceivable that chromatin-borne information participates in alternative splicing. Here we find that elevated levels of trimethylation of histone H3 on Lys9 (H3K9me3) are a characteristic of the alternative exons of several genes including CD44. On this gene the chromodomain protein HP1γ, frequently defined as a transcriptional repressor, facilitates inclusion of the alternative exons via a mechanism involving decreased RNA polymerase II elongation rate. In addition, accumulation of HP1γ on the variant region of the CD44 gene stabilizes association of the pre-mRNA with the chromatin. Altogether, our data provide evidence for localized histone modifications impacting alternative splicing. They further implicate HP1γ as a possible bridging molecule between the chromatin and the maturating mRNA, with a general impact on splicing decisions.

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Figure 1: Histone H3K9 trimethylation (H3K9me3) is enriched on the CD44 alternative exons.
Figure 2: HP1γ regulates alternative splicing of the CD44 transcript.
Figure 3: HP1γ, RNAP II and U2AF65 accumulate on the variant region of CD44 chromatin upon PKC stimulation.
Figure 4: HP1γ bridges chromatin to pre-mRNA.
Figure 5: Cell type–specific distribution of H3K9me3 and HP1γ correlates with variant exon inclusion and RNAP II accumulation.
Figure 6: HP1γ-dependent exon inclusion is guided by an H3K9me3 mark on several genes.
Figure 7: Model for the regulation of CD44 alternative splicing by H3K9me3 and HP1γ.

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Acknowledgements

We thank E. Allemand and J. Seeler for critical reading of the manuscript, and D. Auboeuf (INSERM U590, Centre Léon Bérard, France), P de la Grange (Genosplice Technology, France), V. Ogryzko (CNRS, IGR, Université Paris-XI, France), L. Fritsch and S. Ait-Si-Ali (Université Paris–Diderot, Paris, France) for advice and gifts of reagents. V.S.-A. received fellowships from Région Ile-de-France and L'Association pour la Recherche sur le Cancer. The work was supported by grants from the Agence National de la Recherche and Cancéropôle Ile-de-France.

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  1. Département de Biologie du Développement, Institut Pasteur, Unité de Régulation Epigénétique, Paris, France

    Violaine Saint-André, Eric Batsché, Christophe Rachez & Christian Muchardt

  2. Centre National de la Recherche Scientifique (CNRS), URA2578, Paris, France

    Violaine Saint-André, Eric Batsché, Christophe Rachez & Christian Muchardt

  3. INSERM Avenir, Paris, France

    Violaine Saint-André, Eric Batsché, Christophe Rachez & Christian Muchardt

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  1. Violaine Saint-André
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V.S.-A., E.B. and C.R. designed, performed and analyzed the experiments and prepared the manuscript. C.M. conceived the project and wrote the manuscript.

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Correspondence to Christian Muchardt.

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Saint-André, V., Batsché, E., Rachez, C. et al. Histone H3 lysine 9 trimethylation and HP1γ favor inclusion of alternative exons. Nat Struct Mol Biol 18, 337–344 (2011). https://doi.org/10.1038/nsmb.1995

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