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Putting a halt on PRC2 in pediatric glioblastoma

Nature Genetics volume 45, pages 587–589 (2013)Cite this article

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Two new studies show that the known histone H3 alteration p.Lys27Met in pediatric glioma leads to globally diminished trimethylation at histone H3 lysine 27. The mutant histone H3 acts as a selective inhibitor of the PRC2 chromatin-modifying complex by binding and presumably sequestering it, shedding light on how this variant may contribute to the etiology of these highly malignant brain tumors.

Polycomb repressive complex 2 (PRC2) catalyzes di- and trimethylation of histone H3 at lysine 27 (H3K27me2 and H3K27me3, respectively) and is key for gene silencing from early development to adulthood1,2. PRC2 is heralded as a promising drug target1,3,4,5, given its activity-enhancing alterations6 and aberrant upregulation7 in several types of cancer. Its substrate, histone H3, is remarkably well conserved and has unexpectedly been found to harbor somatic alterations in 31% of pediatric glioblastoma multiforme (GBM)3 and 78% of diffuse intrinsic pontine glioma (DIPG)8,9. These gliomas are highly aggressive and are largely resistant to conventional therapies, with median survival times of about 1 year in both adult and pediatric cases10,11. In DIPGs and GBMs, lysine 27 residues in histones H3.3 and H3.1 were found to be recurrently altered to methionine (p.Lys27Met), whereas, in other GBMs, glycine 34 in histone H3.3 was found to be altered to arginine or valine (p.Gly34Arg or p.Gly34Val, respectively)8,9. The identified mutations in each case affect only 1 of the 16 histone H3 gene copies, indicating that small amounts of mutant histone may be sufficient to cause malignancy through substitution-specific gain-of-function or dominant-negative effects. Two recent studies from David Allis and colleagues12 and from Zhiguo Zhang and colleagues13 offer insight into how the histone H3 p.Lys27Met substitution might profoundly alter gene silencing in pediatric gliomas.

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Figure 1: Histone H3 Lys27Met sequesters and inhibits PRC2 on chromatin.

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Authors and Affiliations

  1. Philipp Voigt and Danny Reinberg are at the Howard Hughes Medical Institute and the Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.,

    Philipp Voigt & Danny Reinberg

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  1. Philipp Voigt
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Correspondence to Danny Reinberg.

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Voigt, P., Reinberg, D. Putting a halt on PRC2 in pediatric glioblastoma. Nat Genet 45, 587–589 (2013). https://doi.org/10.1038/ng.2647

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