DNA Methylation, Nuclear Organization, and Cancer

Abstract

The dramatic re-organization of the cancer cell nucleus creates telltale morphological features critical for pathological staging of tumors. In addition, the changes to the mutational and epigenetic landscape in cancer cells alter the structure and stability of the genome and directly contribute to malignancy. DNA methylation is one of the best studied epigenetic changes in cancer, as nearly every type of cancer studied shows a loss of DNA methylation spread across most of the genome. This global hypomethylation is accompanied by hypermethylation at distinct loci, and much of the work on DNA methylation in cancer has focused on how local changes contribute to gene expression. However, the emerging picture is that the changes to DNA methylation in cancer cells has little direct effect on gene expression but instead impacts the organization of the genome in the nucleus. Several recent studies that take a broad view of the cancer epigenome find that the most profound changes to the cancer methylome are spread across large segments of the genome, and that the focal changes are reflective of a whole reorganization of epigenome. Hallmarks of nuclear reorganization in cancer are found in the long regions of chromatin marked by histone methylation (LOCKs) and nuclear lamina interactions (LADs). In this review, we focus on a novel perspective that DNA methylation changes in cancer impact the global structure of heterochromatin, LADs and LOCKs, and how these global changes, in turn, contribute to gene expression changes and genomic stability.

Keywords: DNA methylation; Large Organized Chromatin Lysine Modifications (LOCKS); cancer; chromatin; lads.

FIGURE 1

DNA methylation is dynamically altered in cancer cells compared to the normal cells. DNA methylation in a region of chromosome 11 between Lymphoblastoid cells (GM12878) and Leukemia cells (K562) shows regions of partially methylated domains (PMD) in the cancer cells, where the methylation levels flatten at around 50% over the region compared to the DNA methylation of the same region in the control sample. There are also regions which do not show any methylation differences (Static) and a DNA block with hypermethylation in the cancer cells. Ref Seq Genes in the region are represented as blue lines below the histogram. This figure was generated using the data from the Epigenome browser of the Roadmap Epigenomics Project (http://epigenomegateway.wustl. edu/browser/).

FIGURE 2

Chromatin rearrangement in the cancer nuclei. In normal differentiated cells, heterochromatin is organized in the nuclear periphery by binding to the nuclear lamina proteins (in blue) and is organized into LADs (red) which overlap significantly with LOCKs (H3K9me2/3 and H3K27me3-green and gray circles). The active domains are tagged by the euchromatin histone marks (pink circles). Cancer cells display nuclear chromatin rearrangement with decreased lamin expression in the lamina, increased euchromatinization, and significant loss of LADs and LOCKs. In cancer, large blocks of DNA termed PMDs (black boxes) coincide to a large extent with LADs and LOCKs. These events can ultimately lead to random DNA recombination events as well as the less stable open chromatin are hotspots for DNA breaks (black dashed lines) (Kind et al., 2013; Luperchio et al., 2014; Feinberg et al., 2016).