期刊
CANCER CELL
卷 24, 期 5, 页码 660-672出版社
CELL PRESS
DOI: 10.1016/j.ccr.2013.10.006
关键词
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资金
- German Cancer Aid [109252, 108456]
- Federal Ministry of Education and Research
- International Cancer Genome Consortium PedBrain, NGFNPlus [01GS0883]
- St. Baldrick's Foundation
- National Institutes of Health [K08NS070926]
- National Health Service
- Center for Children's Brain Tumors at Stanford
- Alex's Lemonade Stand Foundation
- McKenna Claire Foundation
- Cure Starts Now
- Lyla Nsouli Foundation
- Connor Johnson Memorial Fund
- Dylan Jewett Memorial Fund
- Dylan Frick Memorial Fund
- Abigail Jensen Memorial Fund
- Zoey Ganesh Memorial Fund
Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in similar to 50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.
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