Comparative analysis of neuroblastoma: DNA methylation and histone modifications

Aberrant hyper- and hypomethylation are considered crucial steps leading to cancer development and progression in most of the cancers, including neuroblastoma, a childhood tumor derived from sympathetic nervous system cells. DNA methylation changes in neuroblastoma affecting gene expression have been previously described to be essential in regulatory regions. The aim of our study is to characterize the epigenetic profile of the known regulatory regions in neuroblastoma and to understand the relationship between DNA methylation changes, histone modifications and their effect on gene expression.

We analyzed the DNA methylation of eight neuroblastoma cell lines using high-density microarrays and MBD-seq public data. Six of them showed differential methylation in promoters as well as in intragenic and intergenic regions such as enhancers and super-enhancers. We identified 46 genes with hypomethylation of intragenic and promoter regions in neuroblastoma, which also demostrated overexpression. This group of genes is enriched for the genes with high-CpG-density promoters (HCP) bearing histone H3 dimethylation mark at K4 (H3K4me2) and trimethylation mark at K27 (H3K27me3) in neural precursor cells (NPC). Within this group we established that CASZ1 (castor zinc finger 1), RAP1GAP2 (RAP1 GTPase activating protein 2), ACTN2 (actinin, alpha 2) showed hypomethylation of intragenic, promoter, and intergenic regulatory region at the same time.

These genes are also known to be overexpressed in various types of human cancers. To understand the possible correlation between DNA differentially methylated regions with histone modifications in neuroblastoma further analysis of ChIP-seq data for histone profiles (H3K4me3, H3K27ac, and H327me3 marks) is needed.