Associations in cell type-specific hydroxymethylation and transcriptional alterations of pediatric central nervous system tumors

Nat Commun. 2024 Apr 30;15(1):3635. doi: 10.1038/s41467-024-47943-9.

Abstract

Although intratumoral heterogeneity has been established in pediatric central nervous system tumors, epigenomic alterations at the cell type level have largely remained unresolved. To identify cell type-specific alterations to cytosine modifications in pediatric central nervous system tumors, we utilize a multi-omic approach that integrated bulk DNA cytosine modification data (methylation and hydroxymethylation) with both bulk and single-cell RNA-sequencing data. We demonstrate a large reduction in the scope of significantly differentially modified cytosines in tumors when accounting for tumor cell type composition. In the progenitor-like cell types of tumors, we identify a preponderance differential Cytosine-phosphate-Guanine site hydroxymethylation rather than methylation. Genes with differential hydroxymethylation, like histone deacetylase 4 and insulin-like growth factor 1 receptor, are associated with cell type-specific changes in gene expression in tumors. Our results highlight the importance of epigenomic alterations in the progenitor-like cell types and its role in cell type-specific transcriptional regulation in pediatric central nervous system tumors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Central Nervous System Neoplasms* / genetics
  • Central Nervous System Neoplasms* / metabolism
  • Central Nervous System Neoplasms* / pathology
  • Child
  • Cytosine / metabolism
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Epigenomics / methods
  • Gene Expression Regulation, Neoplastic*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Single-Cell Analysis
  • Transcription, Genetic

Substances

  • Histone Deacetylases
  • HDAC4 protein, human
  • Repressor Proteins
  • Cytosine