Epimutations and Their Effect on Chromatin Organization: Exciting Avenues for Cancer Treatment

Abstract

The three-dimensional architecture of genomes is complex. It is organized as fibers, loops, and domains that form high-order structures. By using different chromosome conformation techniques, the complex relationship between transcription and genome organization in the three-dimensional organization of genomes has been deciphered. Epigenetic changes, such as DNA methylation and histone modification, are the hallmark of cancers. Tumor initiation, progression, and metastasis are linked to these epigenetic modifications. Epigenetic inhibitors can reverse these altered modifications. A number of epigenetic inhibitors have been approved by FDA that target DNA methylation and histone modification. This review discusses the techniques involved in studying the three-dimensional organization of genomes, DNA methylation and histone modification, epigenetic deregulation in cancer, and epigenetic therapies targeting the tumor.

Keywords: DNA methylation; cancer; epigenetic inhibitors; epigenetics; histone modification.

Figure 1

Techniques for studying chromatin organization in three-dimensional (3D) space. Steps involved in studying the 3D organization of genomes, (a) A common step in 3C-related techniques is crosslinking chromosomes with formaldehyde and their fragmentation by restriction digestion. The organization of chromatin can be visualized in 3D space using several different detection approaches such as (b) 3C (chromosome conformation capture), (c) 4C (chromosome conformation capture-on-Chip), (d) 5C (chromosome conformation capture carbon copy), (e) Hi-C, (f) Micro-C, (g) ChIA-PET (chromatin interaction analysis paired-end tag sequencing) and (h) Capture-C. This figure was created using BioRender.com access on 14 December 2022.

Figure 2

Factors involved in regulating epigenetic code. Histones undergoes different PTMs such as methylation, acetylation, phosphorylation, ubiquitination and ADP-ribosylation. Writers and erasers are involved in adding and removing PTM, respectively. Readers with specific domains recognizes the PTMs. This figure was created using BioRender.com (accessed on 14 December 2022).

Figure 3

Several levels of organization are present in genomes. Inside the nucleus, DNA (black) is wrapped around nucleosomes (orange), which consist of octamers of core histone proteins H2A, H2B, H3, and H4. Cohesin (red) and CTCF (green) colocalize in the mammalian genomes to form high-order chromatin structures. Chromatin fibers are folded into loops, bringing upstream regulatory elements close to gene promoters. TADs (brown) are formed when chromatin is extruded and insulated in a physical compartment. DNA resides inside chromosome territories (multiple colors), generating non-random arrangements of chromosomes and genes within the nucleus. This figure was created using BioRender.com (accessed on 14 December 2022).