Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma

By P. Lewis, Manuel M Müller, Matthew S. Koletsky, Francisco J. Cordero, Shu Lin, Laura A. Banaszynski, B. Garcia, T. Muir, O. Becher, C. D. Allis. Science, 2013

1,227 citations recorded by the source corpus.

EZ Inhibition Missense mutations in the core constituents of the genome packaging material, chromatin, have been implicated in several of human cancers. Nucleosomes are made up of histones, and a mutation of lysine 27 (K27) to methionine in the N-terminal tail of histone variants H3.3 and H3.1 has been identified in various pediatric gliomas. Lewis et al. (p. 857, published online 28 March; see the Perspective by Morgan and Shilatifard) show that the polycomb enzyme complex, which can epigenetically modify K27 by addition of a methyl group—and which is often a silencing signal—is itself potently inhibited by replacement of the H3.3/3.1 K27 by methionine. The inhibition of the EZH2 subunit causes an overall reduction of K27 methylation. Methionine mutants of other methylated lysine residues in histone H3 cause similar reductions in methylation levels of the cognate lysine, altering the epigenetic profiles of such cancer cells. Mutations of histones in some cancers result in inhibition of enzymes that lay down epigenetic marks on chromatin. [Also see Perspective by Morgan and Shilatifard] Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 through interaction with the EZH2 subunit. In addition, transgenes containing lysine-to-methionine substitutions at other known methylated lysines (H3K9 and H3K36) are sufficient to cause specific reduction in methylation through inhibition of SET-domain enzymes. We propose that K-to-M substitutions may represent a mechanism to alter epigenetic states in a variety of pathologies.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b7ae70f6d8f24c09c9d3c5450c159aed83d0b75b

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In Genetics

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Citations in the corpus

• Epigenetic Determinants of Cancer. (2016, background): “The result is a dramatic loss of H3K27me3 (Chan et al. 2013; Lewis et al. 2013; Shen and Laird 2013), which probably leads to the activation of many genes that can drive tumorigenesis in a particular progenitor cell within a cell compartment.”
• Cancer epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance (2014, background): “Although these tumors harbor a mutation in the K27 residue of histone H3 in only one of multiple alleles encoding this histone (Shen and Laird, 2013), this change appears to act as a dominant-negative effect inhibiting all EZH2 activity resulting in loss of H3K27me3 (Lewis et al., 2013).”
• Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “…mutation in diffuse intrinsic pontine gliomas (DIPGs) results in global H3K27me3 reduction by multiple mechanisms, such as the aberrant PRC2 interactions or hampered H3K27me3 spreading (Bender et al., 2013; Chan et al., 2013; Lewis et al., 2013; Stafford et al., 2018; Harutyunyan et al., 2019).”
• Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. (2013, background): “3 protein (Chan et al., 2013; Lewis et al., 2013; Venneti et al., 2013).”
• Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. (2017, neutral): “Although this was initially correlated to the capacity of H3K27me2/3 to strongly bind and sequester the PRC2 complex, recent data seem to support a model in which H3K27M excludes PRC2 binding, facilitating an aberrant accumulation of acetylated H3K27 (Figure 7A) on the other wildtype copies of histo”