Epigenetic alterations result in harmful mutations

Modifications in methylation patterns lead to harmful genetic mutations

https://www.futuremedicine.com/doi/full/10.2217/epi-2016-0027

Excerpts: "Diverse epigenetic modification patterns can affect the types and frequencies of genetic alterations at the neighboring chromatin regions. Integrative analysis of whole genome sequencing with epigenome sequencing have identified how the epigenetic landscape influences the accumulation of genetic alterations during hepatocarcinogenesis. The analysis also showed that several cancer driver genes are mutated either by genetic or epigenetic alterations. Genetic mutations that are affected or substituted by epigenetic alterations include single nucleotide variant (SNVs) mutations, small insertions and deletions (indels) and DNA copy number variations (CNVs). We have summarized recent findings that demonstrate molecular links between genetic mutations and epigenetic modifications.

 

Because diverse mutational mechanisms are at play during tumorigenesis, the SNV patterns of each tumor are different and reflect the nature of the tumor-inducing conditions. HCC shows high frequencies of C to T, C to A and T to C nucleotide substitutions. Among these, C to T transitions at CpG dinucleotide sequences are caused by the relatively elevated rate of spontaneous deamination of 5-methyl-cytosine in tumors. Thus, the DNA demethylation levels of tumor cells could influence the mutation frequencies induced by the deamination process. In addition, the significant upregulation of the APOBEC family in HBV- and HCV-HCC promotes C to T and C to A mutations by deaminating cytidine to uracil (C to U), coupled with the base excision repair and DNA replication processes. Besides APOBEC enzymes, several cellular and viral proteins also affect base substitutions epigenetically. A methyl-CpG-binding protein, MBD4, can affect the C to T transition rate, probably by regulating accessibility of the methylated C for deamination or repair enzymes.

DNA methylation status also has a strong effect on chromosomal integrity. Global DNA hypomethylation is observed in HCC and can induce activation of transposons and chromosomal instability, thus contributing to the generation of a large number of CNVs during hepatocarcinogenesis. Hypomethylation-associated reactivation of repetitive elements such as LINE-1, ALU and juxtacentromeric SAT2 is frequently observed in HCC along with copy number variations caused by insertions and deletions. Intriguingly, the loss of repetitive DNA appears tightly associated with its hypomethylation.

Acetaldehyde and free radicals generated by metabolizing alcohol induce DNA damage and oxidative stress, which often accelerate monocyte activation and telomere shortening. The alcohol-derived risk factors (acetaldehyde and free radicals) seem to function mainly as a mutagen affecting DNA integrity; however, its role in epigenetic regulation in liver cells is now being discovered."

My comment: We've been taught that epigenetic modifications don't contribute to the DNA but as we can see, this is not the case. It's obvious that changing methylation patterns (also called as methylation profiles) result in changes in DNA sequences. The most typical factors impacting on methylation patterns by abnormal way are oxidative stress, viruses, alcohol, smoking and environmental toxins. Shifting diet types also cause alterations in epigenetic patterns possibly leading to harmful genetic mutations. Life habits are the most significant reason for rapidly increasing repertoire of disease-causing genetic mutations in the human DNA. There are already 208,368 of them at population level. The annual increase was about 20,000. But modern scientists are not aware of beneficial random mutations. That's why there are no mechanisms for evolution. All change in organisms is based on epigenetic regulation of existing biological information OR loss of it. Don't get misled.