Aberrant histone modifications in pediatric brain tumors

Abstract

Epigenetic modifications, particularly histone post-translational modifications (PTMs), are central to pediatric brain tumor pathogenesis, impacting chromatin structure, gene expression, and genomic stability. Disruptions in histone PTMs, especially lysine methylation and acetylation, arising due to histone mutations or aberrant enzyme modulation are critical drivers of oncogenesis. Lysine methylation, catalyzed by histone methyltransferases (KMTs), modulates chromatin interactions and gene expression through activation or repression, depending on the methylation state and the specific histone residue. Key enzymes, including histone methyltransferases and demethylases, and associated proteins exemplify the functions of writers, readers, and erasers in maintaining histone modification balance. Similarly, histone acetylation, a dynamic process regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a crucial role in pediatric brain tumors. Alterations in these components lead to aberrant gene expression and tumorigenesis. Understanding these disrupted processes offers potential for targeted therapies to rewire oncogenic chromatin states and potentially improve patient outcomes.

Keywords: epigenetics; histone acetylation; histone methylation; histone modifications; pediatric.

Figure 1

Regulation of chromatin structure. Schematic representation of chromatin organization. Chromatin is made up of DNA wound around histone proteins. Each histone complex comprises an octamer of histone protein, including H2A, H2B, H3, and H4 (7, 8). Chromatin remodeling, histone mutations, and histone modifications influence chromatin structure. Lysine-specific post-translational modifications of histone H3 tail (A) include methylation (me) and acetylation (ac). Histone modification can be inactive (orange symbols) or active (green symbols). Chromatin accessibility can be influenced by chromatin remodelers, such as the SWI/SNF complexes, which are composed of multiple subunits, such as the SMARCB1 subunit involved in the complex stabilization (9) or the catalytic subunit SMARCA4 (10) (B). Histone mutations (C), including H3K27M or H3G34R, interfere with histone modifications, leading to aberrant chromatin structure and accessibility. Chromosome, chromatin: Created in BioRender. Chung, C. (2025) https://BioRender.com/a87r173.

Figure 2

(A) Schematic of pediatric brain tumor location and characteristic epigenetic modifications. Pediatric brain tumors vary in anatomic location (left) and alterations in expression or mutations in epigenetic regulators (right). Medulloblastoma (MB; green) can be divided into subgroups based on clinical and molecular characteristics. Pediatric high-grade gliomas (pHGG; yellow) can be further characterized by characteristic histone mutations (pink box); diffuse hemispheric gliomas (DHG) are associated with H3G34R/V mutation, or diffuse midline glioma (DMG) are associated with H3K27M mutation. Atypical teratoid/rhabdoid tumor (AT/RT; orange) are most commonly located in the posterior fossa; however, it can be found anywhere in the CNS among pediatric patients. Ependymoma (EPN; blue) can be found in three anatomic compartments, supratentorial (ST), posterior fossa (PF) or spinal (SP). (B) Epigenetic alterations reported in at least one tumor sample from previously reported molecular characterization efforts in MB (–59), pHGG (–64), pediatric low-grade glioma (pLGG; grey) (65) or AT/RT (–70). Mutations or alterations in expression among writers [histone methyltransferases (green text) or histone acetyltransferases (orange text)], erasers [histone demethylases (purple text)], chromatin remodelers, or histone mutations/oncohistone mimics are represented. *Increased expression or mutations in EZHIP reported, or H3K27M histone mutations reported specifically in PFA-EPN. Brain: Created in BioRender. https://BioRender.com/tmiyitf.