Inside the nucleus, DNA, RNA and proteins form chromatin, which packs the DNA to a smaller volume and prevents the long DNA strands from being tangled. The structure of the chromatin is like “beads on a string”. The nucleosome is the “bead”, which is a basic unit of chromatin. Histones, nuclear proteins, can store DNA, modulate chromatin structure, impact gene expression, and regulate almost all DNA metabolic processes through post-translational modification, which includes methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation
[24]. Each nucleosome is composed of a histone octamer, which is composed of two copies each of the core histone H2A, H2B, H3, and H4. H1, which does not contribute to the nucleosome bead, binds to the linker DNA region between nucleosomes, helping pack the chromatin into higher order structures. A chain of nucleosomes is compacted to form a chromosome
[25]. Histone H3s, which have several variants, include H3.1, H3.2, and H3.3. H3.1 is encoded by HIST1H3A-J.H3.2 is encoded by HIST2H3A, HIST2H3C, and HIST2H3D. H3.3 is encoded by H3F3A and H3F3B
[26]. Numerous H3 lysine residues can be post-translationally modified, including acetylated at lysines 9, 14, 18, 23, and 56; methylated at arginine 2 and lysines 4, 9, 27, 36, and 79, and phosphorylated at ser10, ser28, Thr3, and Thr11
[27]. Mutation of H3F3A, including K27M substitution, in which a lysine residue on the histone H3 tail is substituted for a methionine, were discovered in diffused intrinsic pontine glioma(DIPG)
[28]. As the location of the
H3F3A at
lysine 27 is at or near critical regulatory histone residues, therefore, the alternations of mutant K27M on genes, which should be silent, produce widespread aberrant DNA methylation and deregulation of gene expression, impede physiological differentiation and to drive cell transformation
[29]. Furthermore, in the WHO CNS tumor classification 2016, the principle of an integrated diagnosis was introduced with the combination of histological and molecular features, exemplified in the novel entity “diffuse midline glioma, H3K27M- mutant”
[30]. The mutation in HIST1H3B-C, have been detected in approximately 10% of DIPG
[31]. Another mutation of H3F3A, encoding a glycine 34 to arginine or valine (G34R/V) substitution, is reported in a smaller portion of pediatric and young adult high-grade astrocytoma
[9]. H3F3G34 mutations may drive pediatric GBM through mismatch repair (MMR) deficiency
[32] and upregulation of v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian) (MYCN)
[33].