Glioblastoma (GBM) is the most aggressive primary brain tumor in human. Recent 
studies on high-grade pediatric GBM have identified two recurrent mutations 
(K27M and G34R/V) in genes encoding histone H3 (H3F3A for H3.3 and HIST1H3B for 
H3.1). The two histone H3 mutations are mutually exclusive and give rise to 
tumors in different brain compartments. Recently, we and others have shown that 
the histone H3 K27M mutation specifically altered the di- and tri-methylation of 
endogenous histone H3 at Lys27. Genome-wide studies using ChIP-seq on H3.3K27M 
patient samples indicate a global reduction of H3K27me3 on chromatin. 
Remarkably, we also found a dramatic enrichment of H3K27me3 and EZH2 (the 
catalytic subunit H3K27 methyltransferase) at hundreds of gene loci in H3.3K27M 
patient cells. Here, we discuss potential mechanisms whereby H3K27me3 is 
enriched at chromatin loci in cells expressing the H3.3K27M mutation and report 
effects of Lys-to-Met mutations of other well-studied lysine residues of histone 
H3.1/H3.3 and H4 on the corresponding endogenous lysine methylation. We suggest 
that mutation(s) on histones may be found in a variety of human diseases, and 
the expression of mutant histones may help to address the function of histone 
lysine methylation and possibly other modifications in mammalian cells.