Epigenetic modifications and their roles in pediatric brain tumor formation: emerging insights from chromatin dysregulation

Abstract

Pediatric brain tumors, the most devastating cancers affecting children, are believed to originate from neural stem/progenitor cells in developing brain. In precise timing and specific regions during the brain development, chromatin deregulation plays crucial roles in redirecting normal neuronal differentiation pathways toward tumorigenesis. Indeed, epigenomic abnormalities are thought to be more important for brain tumor formation especially in children than adults, as pediatric brain tumors generally exhibit fewer genetic mutations compared to adult brain tumors. Given the small number of mutations, targeting such limited alterations involved in cancer epigenomes is expected to be more effective in pediatric brain tumors. The mechanisms of cancer epigenomes include mutation or dysregulation of chromatin remodelers, histone modifiers, histones themselves, and DNA methylation enzymes. Furthermore, genomic rearrangements and/or higher-order chromatin topology also contribute to these epigenomic mechanisms. These mechanisms are commonly observed in various types of pediatric brain tumors. However, alterations in chromatin regulatory factors differ across tumor types, reflecting the unique epigenetic landscapes shaped by their tumor origins. Accordingly, clarifying their functional similarities and differences across tumor types could offer valuable insights for finding new therapeutic strategies. Thus, this review article focuses on elucidating how pediatric brain tumors arise from epigenomic deregulation and what epigenetic molecules or mechanisms could serve as therapeutic targets.

Keywords: DNA methylation; chromatin remodeler; epigenetics; extrachromosomal DNA (ecDNA); fusion oncogene; genomic rearrangement; histone modification; pediatric brain tumor.

Figure 1

Overview of epigenetic regulatory mechanisms in pediatric brain tumors and their tumor-type-specific distribution. (a) Pediatric brain tumors develop through various kinds of epigenetic mechanisms, including dysregulation of chromatin remodelers, histone modifiers, histone mutations, and DNA methylation. Genomic rearrangements may generate gene fusions, extrachromosomal DNA (ecDNA) or alterations in higher-order chromatin topology which also often contribute to the cancer epigenome. (b) Schematic illustration graphically depicts the anatomical origins and distribution of each tumor type (26), including Atypical teratoid/rhabdoid tumor (AT/RT) (19), Embryonal tumors with multilayered rosette (ETMR) (25), Wingless medulloblastoma (WNT-MB) (20), Sonic hedgehog medulloblastoma (SHH-MB) (20), Group 3 medulloblastoma (G3-MB) (20), Group 4 medulloblastoma (G4-MB) (20), Supratentorial ependymoma (ST-EPN) (23), Posterior fossa A ependymoma (PF-EPN-A) (23), Circle area is proportional to the number of new diagnoses at each anatomical location. Posterior fossa B ependymoma (PF-EPN-B) (23), Diffuse midline glioma (DMG) (21, 22), High grade glioma (HGG) (21, 22), Low grade glioma (LGG) (24). This image also shows major epigenomic alterations associated with pediatric brain tumors discussed in this study.

Figure 2

Dysregulation of chromatin remodelers in pediatric brain tumors. (a, b) Structure of ATP-dependent chromatin remodelers, the SWI/SNF complex (upper panel in a) and CHD7 (upper panel in (b)). The core subunits of the SWI/SNF complex, SMARCB1 and SMARCA4 are mutated in human patients bearing AT/RTs and MBs (111) (lower panels in (a)), while mutations of CHD7 are found in MBs (38) (lower panel in (b)). The known functional domains of the respective proteins are highlighted and labeled with their names. The patterns of genetic mutations are shown in the figure. Data sourced from previous studies (38, 111) and St. Jude Cloud Pediatric Brain Tumor Portal (https://pbtp.stjude.cloud). (c) Schematic diagram of regulation of chromatin compaction by ATP-independent pioneer factors.

Figure 3

Failure of appropriate histone modification in pediatric brain tumors. (a) Inhibition of chromatin opening by loss of HAT function (e.g., CREBBP) (upper left panel) and aberrant activation of HDAC (upper right panel). Pathogenic loss-of-function (LOF) mutations of CREBBP in MB (38, 51) (lower panel). (b) Histone H3 demethylation by loss of KMT function (upper left panel) and EZHIP activation (upper middle panel) for tumorigenesis. Conversely, in some tumors, EZH2 activation often functions to prevent proper differentiation and contributes to oncogenesis (upper right panel). Mutations of KMT2D found in MBs (lower panel) (38). (c) Histone H2A ubiquitination regulating cancer-related genes. BCOR loss activates Igf2 oncogene (upper left panel), while BMI activation inhibits tumor suppressor genes (upper right panel). LOF mutations of BCOR in MBs (68) (lower panel). The known functional domains of the respective proteins are highlighted and labeled with their names. The patterns of genetic mutations are shown in the figure. Data sourced from previous studies (38, 51, 68) and St. Jude Cloud Pediatric Brain Tumor Portal (https://pbtp.stjude.cloud).

Figure 4

Histone mutations and the resulting abnormalities in histone modifications. (a) H3K27M-mutant H3 exhibits higher binding affinity than wild-type histone H3 to PRC2, leading to global reduction of PRC2-mediated H3K27me3 (left). Decreased H3K27me3 induces expression of pioneer factors (e.g., NEUROD1, ASCL1) (middle) that subsequently cooperate with enhancer/super-enhancers to further enhance abnormal chromatin accessibility (right). (b) H3.3G34R represses a lysine 36 methyltransferase SETD2, leading to low H3.3K36me3 levels, which disrupts interaction between a repressor ZMYND11 and H3.3. Reduced ZMYND11 function, in turn, activates forebrain progenitor genes involved in hemispheric pHGG formation.

Figure 5

DNA methylation dysregulation associated with pediatric brain tumor formation. (a) Upregulated DNMTs methylate CpG islands of genomic DNA and silence transcription in SHH-MB and ETMR. (b) Global DNA hypomethylation due to EZH2 inactivation induces oncogene expression (e.g., PCDH7) to drive DMG tumorigenesis. (c) DNA hypermethylation caused by EZH2 and DNMTs blocks the binding of transcription factors (e.g., NEUROG2/NEUROD1), repressing differentiation-associated genes (e.g., EBF3) and maintaining stemness of AT/RTs.

Figure 6

Epigenetic dysregulation induced by genomic rearrangement in pediatric brain tumors. (a) Enhancer hijacking; oncogenes (e.g., GFI1) are aberrantly activated by enhancers of other genes (e.g., BARHL1/DDX31) via deletion, inversion, tandem duplication due to genomic rearrangement in G3/G4-MBs (left panel). Topological associated domains and chromatin looping can also lead to the enhancer hijacking (right panel). (b) Fusion oncoproteins; ZFTA::RELA (left panel) and YAP1::MAMLD1 (right panel) observed in ST-EPNs expressed from these fusion genes modulate chromatin states in combination with other chromatin regulators. (c) Structural rearrangements leading to ecDNA formation may juxtapose oncogenes with ectopic enhancer elements, leading to transcriptional dysregulation of the ecDNA-amplified oncogene.