Histone H3.3 (H3F3A) (H3F3A)

Histone H3.3, encoded by the H3F3A gene, is a highly conserved histone variant that is incorporated into chromatin throughout the cell cycle, distinguishing it from canonical histones that are deposited only during DNA replication (UniProt P84243). It is primarily associated with transcriptionally active regions and plays a vital role in maintaining genome stability and regulating gene expression (Wu et al., 2012). Mutations in H3F3A, particularly the K27M and G34R/V substitutions, are recognized as 'oncohistones' and serve as definitive drivers in pediatric high-grade gliomas, including diffuse intrinsic pontine glioma (DIPG) (Lewis et al., 2013). These mutations exert dominant-negative effects; for example, the K27M mutation inhibits the Polycomb Repressive Complex 2 (PRC2), leading to a global loss of H3K27 trimethylation and subsequent aberrant gene expression. Therapeutic strategies are currently focused on small molecules that can bypass or reverse these epigenetic alterations, such as the dopamine receptor antagonist and ClpP agonist ONC201, which has shown clinical activity in H3 K27M-mutant tumors (ClinicalTrials.gov). Other approaches include the use of HDAC inhibitors or EZH2 inhibitors to restore the epigenetic balance disrupted by these histone mutations. Additionally, H3.3 mutations are found in mesenchymal tumors like chondroblastoma, where the K36M mutation disrupts H3K36 methylation patterns.

Other names

H3 histone family member 3AH3.3AH3F3H3-3AHistone H3.3

Epigenetic modulation through inhibition of histone methyltransferases or restoration of histone acetylation/methylation balance