Epigenomics: Opening the Black Box of Cancer

The epigenome is composed of chemical markers and proteins that can attach to DNA and direct the function of gene regulatory elements, controlling the production of proteins in specific cells, among other roles. Common epigenomic modifications include methylation of the nucleotide cytosine and histones or acetylation and phosphorylation of histones. All of these modifications do not change the genome sequence, but they do change the way the cell uses the same set of genetic codes, thus altering phenotypes and metabolic activities. The epigenome is also inheritable.

Epigenetic modifications provide a stable mechanism by which cells with the same genotype can regulate their gene expression and exhibit different phenotypes. Studies have found that stresses such as unhealthy lifestyles and environmental factors can lead to epigenome changes, which may be detrimental to the body. Alterations in epigenomic patterns may lead to different clinical phenotypes; the effects of these modifications have been studied in psychiatric disorders, obesity, and cancer.

An Overview of Epigenetic Mechanisms (Kobow K et al., 2020)

Epigenetics of Cancer

With the identified regulatory role of epigenetic changes in human tumors being explained, cancer has shifted toward genomic and epigenomic disease changes. Epigenetic changes have been shown to drive cancer phenotypes in concert with genetic alterations. For example, in vitro studies have found that the DNA methylation inhibitor (5-aza-2'-deoxycytidine) in combination with vitamin C administration synergistically inhibits proliferation and increases apoptosis by enhancing endogenous retroviral (ERV) demethylation. Furthermore, these epigenetic landscape topologies can be used as biomarkers, and their potentially reversible nature has been regarded as an attractive prospect in the field of epigenetic therapeutics. Just as metformin, which can dynamically reshape the epigenomic landscape of cancer, is used to decode cancer biology.

Innovative Epigenomics Approaches

The field of epigenomics continues to expand rapidly, thanks to a variety of array-based and sequencing-based technologies to decipher the epigenetic code. They allow researchers to understand how the epigenome contributes to disease development by mapping and comparing the epigenomes of various types of cells or tissues.

The basic tools for analyzing DNA methylation are DNA digestion assays and bisulfite sequencing. Unmethylated DNA is cleaved by methylation-sensitive nucleic acid endonucleases. Digested DNA can be analyzed by sequencing or microarray to map methylation sites.

For histone modifications, chromatin immunoprecipitation (ChIP) is a widely used technique for identifying localized post-translational modifications in histone tails and monitoring changes in modifications in response to different stimuli. ChIP can also be used to analyze the binding of transcription factors and enzymes to chromatin, using antibodies specific to the factor of interest.

Chromatin structure can also be studied using chromatin conformation capture (3C) technology, which identifies chromatin regions that are physically associated together, such as promoters and enhancers.

Epigenetic landscapes can also be studied by chromatin accessibility methods. transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) accesses chromatin open regions to obtain epigenetic modification during cell development or diseases.

Sequencing has higher resolution and throughput compared to microarrays and is one of the most commonly used techniques to study DNA and RNA epigenetic modifications. The modified composition of single nucleotides can now be read out directly using long-read sequencing techniques (Pacbio SMRT and Nanopore Platforms).

EWAS and GWAS share many analytical approaches that allow the study of a large number of epigenetic modifications in a large number of patients and controls to detect abnormal modification signals at the population level. The interpretation of EWAS is more complex, and there is still a need to develop more sophisticated analytical tools and techniques to account for potential biases and factors that may affect the interpretation of results.

The Future

Drugs that work by targeting epigenetic mechanisms are already available. A promising trend for the future is the combination of epigenetic drugs with other compounds that can better control the bidirectional relationship between epigenetic switches and metabolism to address disease progression. New epigenetic-based diagnostic tests could also help classify individuals with chronic diseases, prescribe drug treatments that fit the patient's profile, minimize possible cytotoxicity or adjust dietary requirements to improve the individual's health.