The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression
- Kui-Ming Chan1,5,
- Dong Fang1,5,
- Haiyun Gan1,
- Rintaro Hashizume2,
- Chuanhe Yu1,
- Mark Schroeder3,
- Nalin Gupta2,
- Sabine Mueller2,
- C. David James2,
- Robert Jenkins4,
- Jann Sarkaria3 and
- Zhiguo Zhang1,6
- 1Department of Biochemistry and Molecular Biology,
- 2Department of Neurological Surgery, University of California at San Francisco, San Francisco, California 94143, USA;
- 3Department of Radiation Oncology,
- 4Department of Laboratory Medicine Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA
Abstract
Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is ∼1 yr. Here we show that the levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis.
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Footnotes
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↵5 These authors contribute equally to this work.
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↵6 Corresponding author
E-mail: zhang.zhiguo{at}mayo.edu
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.217778.113.
- Received March 13, 2013.
- Accepted April 1, 2013.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press