Losing DNA methylation at repetitive elements and breaking bad

Abstract

Background: DNA methylation is an epigenetic chromatin mark that allows heterochromatin formation and gene silencing. It has a fundamental role in preserving genome stability (including chromosome stability) by controlling both gene expression and chromatin structure. Therefore, the onset of an incorrect pattern of DNA methylation is potentially dangerous for the cells. This is particularly important with respect to repetitive elements, which constitute the third of the human genome.

Main body: Repetitive sequences are involved in several cell processes, however, due to their intrinsic nature, they can be a source of genome instability. Thus, most repetitive elements are usually methylated to maintain a heterochromatic, repressed state. Notably, there is increasing evidence showing that repetitive elements (satellites, long interspersed nuclear elements (LINEs), Alus) are frequently hypomethylated in various of human pathologies, from cancer to psychiatric disorders. Repetitive sequences' hypomethylation correlates with chromatin relaxation and unscheduled transcription. If these alterations are directly involved in human diseases aetiology and how, is still under investigation.

Conclusions: Hypomethylation of different families of repetitive sequences is recurrent in many different human diseases, suggesting that the methylation status of these elements can be involved in preservation of human health. This provides a promising point of view towards the research of therapeutic strategies focused on specifically tuning DNA methylation of DNA repeats.

Keywords: Alzheimer’s disease; Autism spectrum disorder; Cancer; DNA hypomethylation; Hereditary diseases; ICF syndrome; LINE-1; Neuropsychiatric disorders; Repetitive DNA; Satellites.

Fig. 1

Characteristics and localization of repetitive DNA. A Distribution of repetitive elements along the chromosome. B Schematics showing the epigenetic characteristics of heterochromatin with methylated cytosines and nucleosomes containing histone H2 di- or tri-methylated on lysine 9 (H3K9me3). Heterochromatic protein 1 (HP1) binds H3K9me3. C Schematic representation of the nucleus showing the organization and localization of heterochromatic REs which are mainly distributed in the nuclear periphery, in the perinucleolar space or as heterochromatic bodies like the case of pericentromeres

Fig. 2

Potential contributions of hypomethylated REs to carcinogenesis. As opposed to normal cells, cancer cells are characterized by cytosine methylation loss at repetitive DNA. This alteration can affect cell behaviour and contribute to cancer initiation/progression in several ways. The hypomethylated REs can be regulators of oncogenic lncRNAs and, thus, induce their abnormal transcription. TEs or satellite DNA, once hypomethylated, can be also transcribed potentially affecting several processes and leading to genomic and chromosome stability. Furthermore, hypomethylation of REs could affect chromosome structure making it more fragile and prone to breaks, recombination and even to the weakening of centromere function. By changing the compaction degree of the chromatin, hypomethylation of REs also affects nucleus size and organization which, we believe, could dangerously compromise cells, though this research field has not been well explored