Abnormal DNA Methylation Induced by TET Repression

Inflammation is one of the ways that your body fights off infections, or begins healing itself after injury. When a pathogen enters the body, cells release chemical signals that call for white blood cells to destroy the threat. This response may cause damage to the cell, and result in a brief swelling of the afflicted area.

The real problem occurs when the inflammation lingers for more than a few days. Chronic inflammation over time can damage healthy cells, but it can usually be treated with steroids or NSAIDs. Left untreated, it can result in diabetes, heart disease, or even cancer.

It is known that chronic inflammation can have an effect on certain epigenetic modifications like DNA methylationbut how exactly it occurs remains a bit ambiguous. In a study published in the Journal of Clinical Investigation,scientists from the National Cancer Center Research Institute in Tokyo wanted to elaborate on the relationship between chronic inflammation and DNA methylation.

Specifically, they focused on how constant inflammation over time can alter the activity of DNA methyltransferases(DNMTs), and TETgenes, both of which are responsible for monitoring DNA methylation levels in cells.
DNMTs are enzymes that allow the transfer of a methyl group to the 5th cytosine of the DNA, typically resulting in silencing gene expression. TET genes work in opposition to DNMTs, and effectively demethylate the DNA to help regulate gene expression.

The research team led by Dr. Hideyuki Takeshima began the experiment by infecting 6 week old mice with a bacterium called Helicobacter felis (H. felis) to induce inflammation for either 34 or 86 weeks. They took gastric and colon epithelial cell samples after the infection period, and analyzed them for DNMT, TET activity, and miRNA activity.

In addition to the mouse samples, the team obtained 12 gastric tissue samples from human volunteers, and infected 6 of those samples with a bacterium called Helicobacter pylori (H. pylori)to induce inflammation.

In order to evaluate the tissue samples, the team isolated the nuclear proteins using the EpiQuik Nuclear Extraction Kit. Next, they quantified the DNMT levels in the tissues using the EpiQuik DNMT Activity/Inhibition Assay Ultra Kit.
They discovered that chronic inflammation had activated a metabolic pathway called NF-kB, which plays an important role in a cells immune response to an infection. This pathway noticeably repressed TET activity, which in turn increased expression of DNMT and resulted in an abnormal increase of DNA methylation levels.

The team knocked down the TET genes and noticed there were still abnormal levels of DNA methylation. They determined that the combination of TET repression from NF-kB pathway activation, and exposure to nitric oxide helped to increase DNMT activity, leading to erratic DNA methylation.

Understanding how chronic inflammation can affect the body on a molecular level is an important task. The results obtained in this study suggest that nitric oxide and NF-kB inhibitors may help prevent the damaging effect of long term inflammation. Further research is needed to expand upon the ways to prevent aberrant DNA methylation with hopes of limiting disease development.

Source:
Takeshima H, Niwa T, Yamashita S, et al. (2020). TET repression and increased DNMT activity synergistically induce aberrant DNA methylation. J Clin Invest.