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RYGB and DNA

Gastric bypass induces changes in DNA methylation

Credit: ApersOn
RYGB surgery decreases the genome-wide pre-surgery distance between promoter-specific DNA methylation

A recent study, Roux-En Y Gastric Bypass Surgery Induces Genome-Wide Promoter-Specific Changes in DNA Methylation in Whole Blood of Obese Patients publish in PlosOne has concluded that the Roux-en-Y gastric bypass (RYGB) surgery influences genome-wide promoter-specific DNA methylation in obese patients and these promoters are involved in the initiation and regulation of gene transcription.

They explain that RYGB surgery decreases the genome-wide pre-surgery distance between promoter-specific DNA methylation in whole blood of obese patients and the findings could form the basis for further investigations to unravel the molecular effects of gastric bypass surgery.

It is believed that epigenetic modifications play an important role in the development of and predisposition to metabolic diseases, including type II diabetes and obesity, and DNA methylation has been proposed to play a critical role in many cellular and biological processes.

In order to examine the influence of RYGB surgery on DNA methylation in patients, the researchers measured promoter-specific DNA methylation in whole blood in 11 obese patients both before and six months after RYGB surgery, as well as once only in a control group of 16 normal-weight men. In addition, body weight and fasting plasma glucose were measured after an overnight fast.

The researchers examined the Euclidean distance of all promoters (n=16,724) was estimated for both pre-surgery time point vs. control group and post-surgery time point vs. control group. These distances were then compared by means of a pairwise t test.

They also looked at the pre-surgery DNA methylation of the 16,724 promoter regions was compared with that obtained at six month after RYGB. All significant promoter hits revealed by this pre/post comparison were then subjected to an additional Euclidean distance analysis.

Outcomes

Following RYGB surgery obese patients reduced their body weight by about 24%. However, patients’ weight remained significantly higher compared to the normal-weight group. Fasting plasma glucose levels were lower at six month after RYGB compared with baseline values (- 16%), with no statistical difference between obese patients at the post-surgery time point and normal-weight controls.

The mean genome-wide Euclidean distance between promoters of obese patients at six month after RYGB surgery and controls was significantly shorter, as compared to that at baseline (p<0.001, Figure 1, left panel). An additional analysis demonstrated that at six month after RYGB surgery, the DNA methylation of 51 promoters was significantly different from corresponding pre-surgery values (28 were upregulated and 23 were downregulated, p<0.05 for all promoters).

Figure 1: Mean (± SEM) genome-wide Euclidean distance between promoter-specific DNA methylation of obese patients and controls before and at six month after Roux-en Y gastric bypass surgery. The left panel illustrates the mean Euclidean distance at genome-wide scale, whereas the right panel shows the mean Euclidean distance at single-gene promoter scale. A two-tailed p-value <0.05 was considered significant.

The mean DNA methylation of these 51 promoters was also more similar after surgery to that of controls, as compared to that at baseline (p<0.0001; Figure 1, right panel). When controlling for the RYGB surgery-induced drop in weight (-24% of respective baseline value) and fasting plasma glucose concentrations (-16% of respective baseline value), the DNA methylation of only one out of 51 promoters (~2%) remained significant at the post-surgery time point. An enrichment analysis of GO-terms biological processes using DAVID functional analysis revealed an enrichment for genes involved in metabolic processes (p<0.05).

“Although our study findings indicate that the whole blood DNA methylation of promoters in obese patients goes towards methylation levels of normal-weight subjects at six month after RYGB surgery, they do not allow firm conclusions as to whether promoter-specific DNA methylation per se has been reset to physiological values…” the authors conclude. “Our results show that RYGB surgery concurs with changes in methylation at DNA sites that are typically involved in the initiation and regulation of gene transcripts. Bearing in mind that we did not measure whole-blood gene transcription, an important next step is to investigate if the RYGB-induced differences in promoter-specific DNA methylation in whole blood are associated with differences in gene expression.”

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