The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 16 No. 10 • November 2013


Epigenetic Changes in Expression
of Genes via DNA Methylation

Part II

In the May 2013 issue of this newsletter, we published an article on “Methylation, a major mechanism regulating gene expression, changes with age, revealing dynamic landscape.” We continue that here with new data. In our May article, we discussed how methyl donors (such as s-adenosylmethione (SAMe), folic acid, choline, and methionine) are part of a system that, under the regulation of DNA methyltransferases either adds a methyl group to or removes a methyl group from a specific site on DNA histones which controls whether a gene can be transcribed (turned on) or silenced (turned off). With the discovery of this process, much exciting new research has already been and continues to be published.

Changes in Age-dependent Epigenetic Parameters by Exercise in Rat Hippocampus

New research on the effect of exercise on DNA methylation are being published. One paper1 reports on the effects in male Wistar rats at ages 3 and 20 months old of engaging in two exercise protocols on a treadmill, one for a single session of 20 minutes of exercise and the other chronic treadmill exercise (20 minutes running each day for 2 weeks). The results showed that the 20 month old (and 20 months qualifies as aged if you’re a rat) had lower histone H3-K9 methylation levels (about 50%) as compared to the 3 month old rats. Also, the levels of DNMT1 (DNA methylatransferase 1) were significantly diminished in the aged animals by about 25%. The level of DNMT3b (DNA methyltransferase 3b) was not modified by age.

These results are consistent with the data from other studies as noted by the authors.1 They explain that there is a “genome-wide tendency to DNA hypomethylation in multiple vertebrate organs during aging process. In addition, the age-related global hypomethylation is related to DNMT1 deficits in senescent human fibroblasts. However, studies reporting DNMT content in the brain during aging process are lacking.”

Further results1 showed that “[w]hen measured 1 h after [single] session ended, young adult exercised rats exhibited lower levels of DNMT3b (about 30%) when compared to its sedentary group [young adult rats not exercised] (p=0.042); while no delayed (18 h) effects of exercise were observed.” This change was not observed in the aged rats. There were no changes in DNMT3b as a result of chronic exercise in all groups. Likewise for DNMT1, the acute (single session) of exercise acutely diminished this DNA methyltransferase by about 45% in the hippocampi of 3 month old rats (p<0.001) without any changes 18 hours after exercise. Again, this change was not observed in the aged rats. Meanwhile, there was no significant effect of the chronic exercise regimen on DNMT1 in either young adult or aged rats.

The transient effect of decreased DNMT3b after acute exercise implies that, as suggested by the authors of a different (earlier) study,2 DNA hypomethylation is an early event in contraction-induced gene activation. The second study2 also found that the promoter of genes with exercise-induced increased expression (PGC-1alpha, PDK4, PPAR-delta) were hypomethylated (had decreased methylation after as compared to before exercise) in human healthy sedentary subjects following acute exercise. Hypo­methylation supports the notion that there was greater expression of those genes. Note that PGC-1alpha is a “master” gene that controls mitochondrial biogenesis.

The results1 also support the idea that there is a decrease in histone methylation in many genes with an increase in others occurring as part of the aging process.

DNA Methylation Deficits in Memory with Age Can Be Reversed by Increasing a DNA Methyltransferase

A recent paper3 reports that aged mice have decreased expression of a DNA methyltransferase (DNMT3a2) that results in memory deficits and that restoration of the expression of this enzyme can reverse the memory deficits.

One of the tests used by the researchers to detect the memory defect was by exposing the mice to a tone followed by a foot shock. When exposed to the tone in a different context 24 hours later, the old mice froze with fear much less often than the young mice, indicating that the memory of the old mice functioned less well (e.g., they were less likely to remember the warning tone). Using a recombinant adeno-associated virus to deliver the gene for DNMT3a2, the scientists were able to restore the memory of the old mice.

The authors3 hypothesized that the loss of the DNA methyltransferase resulted in decreased methylation of and less expression of the enzyme’s target genes. (In this case, the DNA methylation acted as a transcriptional activator, increasing gene expression, although DNA methyl­ation can in other circumstances act as a transcriptional suppressor, decreasing gene expression—yup, it’s complicated.) See also reference #4, which is the commentary on paper #3.

Methylation Changes Found in Night Shiftworkers

Finally, we have another new paper5 that reports on a study of DNA methylation changes in 10 randomly selected women from an initial group of 17 with long histories of night shiftwork that were compared to 10 female dayworkers. The researchers found widespread methylation changes at imprinted genes in the night shiftworkers. (Imprinted genes are the alleles of genes, which are expressed depending upon the parent of origin. “Loss of monoallelic expression at imprinted genes, known as loss of imprinting (LOI), has been associated with various cancer types and may play a role as an early driver in tumor development.”5) Among the genes with methylation changes, the paper reported, were many with roles in circadian clock pathways that have been linked to cancer risk.

The authors propose that, although it has not been proven, long-term shiftwork may induce changes in methylation by perturbing the normal circadian exposure to light. “Interestingly, the magnitudes of methylation changes observed are comparable to methylation changes which have been attributed to occupational exposures to low-dose benzene and polycyclic aromatic hydrocarbons.” Such exposures can be carcinogenic at high enough doses.

Hypomethylation to Resensitize Diffuse Large B-Cell Lymphoma to Chemo­therapy; Restores Tumor Suppressor Gene Activity

We have written about the exciting new finding that DNA hypomethylation has been shown in some cancers to restore the activity of tumor suppressor genes that have been silenced by hypermethylation.6 Hypomethylating drugs such as azacytidine are being used in early trials to restore the sensitivity of cancers that have become chemotherapy resistant. In a new paper,6 researchers used diffuse large B-cell lymphoma cell lines to study the use of the hypomethylation drug azacytidine to reactivate the SMAD1 gene that resensitized the cells to standard chemotherapeutic treatment after they had become resistant.

In another very recent paper,7 the authors review the new work on DNA hypermethylation that silences tumor suppressor genes and the discovery of agents that can reactivate these silenced genes, such as drugs (for example, azacytidine) or natural compounds acting via different mechanisms to inhibit DNA methyltransferases, thus decreasing methylation, that includes curcumin, EGCG, resveratrol, parthenolide, and others).

References

  1. Elsner et al. Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: A preliminary study. Exp Gerontol. 48:136-9 (2013).
  2. Barres et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 15:405-41 (2012).
  3. Oliveira et al. Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities. Nat Neurosci. 15(8):1111-3 (2012).
  4. Su & Tsai. DNA methylation in cognition comes of age. Nat Neurosci. 15(8):1061-2 (2012).
  5. Jacobs et al. Jacobs et al. Methylation alterations at imprinted genes detected among long-term shiftworkers. Environ Mol Mutagen. 54:141-6 (2013).
  6. Clozel et al. Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov. 3(9):1-18 (2013).
  7. Singh et al. DNA methyltransferase inhibitors as epigenetic therapy for cancer. Curr Cancer Drug Targets. 2013 Mar. 18 [Epub ahead of print].

Featured Product

Ingredients in this Article

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator