Epigenetic Study Identifies a Novel Biomarker for an Elusive Bladder Disease

Researchers examine the biological meaning of upregulated α-OG associated with interstitial cystitis

bladder disease and epigenetics

Running to the restroom is normal when you’ve got a full bladder ready to burst. But constantly feeling the urge to go multiple times a day can be uncomfortable and debilitating, especially if it’s accompanied by severe pelvic pain. For those suffering from interstitial cystitis (also called painful bladder syndrome), this is an unfortunate reality – one that is often misdiagnosed and challenging to treat.

In a recent study published in Scientific Reports, researchers from the US and Korea may have identified a novel biomarker for interstitial cystitis (IC) that could potentially aid in diagnosing the disease as well as in developing new treatment therapies for it. Their findings were achieved through DNA methylation analysis.

Epigenetic mechanisms have been found to play important roles in a variety of health conditions. DNA methylation is the most well characterized epigenetic modification and it typically acts to suppress gene expression. Several studies have implicated aberrant methylation in the etiology of common human disorders such as diabetes, cancer, schizophrenia, and many more. In previous articles, we’ve discussed how DNA methylation analysis was used to identify the risk for developing breast cancer and type 2 diabetes. In fact, evaluating methylation status has been useful in many studies looking to identify promising diagnostic biomarkers.

If you’re not familiar with IC, it’s a chronic painful bladder condition of which no definable cause can be found. In the US alone, IC affects between 2-4% of men and 3-6% of women. With a wide range of symptoms and severity, IC is often confused at first with other ailments such as a urinary tract infection, kidney stones, or cancer. A diagnosis is usually made after all other treatable conditions are ruled out. The symptoms of this condition can be so extreme — like going to the bathroom as much as 60 times a day — that they negatively impact a person’s social life, sleep, and even their ability to work.

Because there is no cure for IC, most treatments are aimed at controlling the symptoms. Sometimes it takes a while for a patient to find a solution that offers good relief. However, getting treatment early is important. Succumbing to the urge to urinate all the time can eventually cause the bladder to shrink, only intensifying the necessity to go to the bathroom more frequently.

To identify any IC biomarkers, the researchers here decided to examine urine as a bio-resource; mostly because of its proximity to the disease. Long considered just an expendable composite of waste and byproduct, urine has been recognized more recently as an untapped biomarker source with prospective use for disease diagnosis. Scientists are now looking into the metabolic properties of urine as a possible indicator of certain medical disorders.

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This study focused on Kreb cycle intermediate α-oxoglutarate (α-OG) due to its heightened amount in IC patients and its reported role in suppressing the proliferation of immortalized normal human bladder epithelial cells. The goal was to learn more about the mechanism of IC by investigating the occurrence of upregulated α-OG and its biological significance.

“While bladder metabolism is altered in the IC, it is unknown if metabolic biomarkers like α-OG are biologically active in urine,” the authors indicated. “The assumption is that the microenvironment causes the metabolic changes which then alter the oxygen states and metabolites. Yet the metabolites are the products of this disturbed metabolism, so it’s likely that they could be mediating the epigenetic alteration seen in the IC bladder.”

Analysis was performed using epigenome-wide DNA methylation profiling accompanied by subsequent biochemical approaches. The results showed that AT-rich interactive domain 1 A (ARID1A), a key chromatin remodeler, was hypomethylated and upregulated by α-OG treatment. In addition, two commercial assays indicated that α-OG almost entirely suppressed ten-eleven translocation (TET) activity, but did not affect DNA methyltransferase (DNMT) activity.

According to the report, the findings are consistent with IC patient clinical observations. For instance, a typical feature of the condition is thin epithelium tissue lining the bladder wall. Plus, previous mechanistic studies have demonstrated that IC bladder epithelial cells have suppressed proliferation and cell cycle arrest. Based on this, the researchers believe that α-OG may possess an active biological function in addition to being a novel urinary metabolite associated with IC.

The overall outcome from the analysis suggests that α-OG is involved in epigenetic remodeling through its influence on ARID1A and TET expression in the bladder. Further investigation is needed to validate α-OG’s role in IC. However, this study might be a step in the right direction for a disease that has been called an unsolved enigma in the field of urology.

The researchers stated, “We believe that additional attempts to validate the epigenetic regulation of α-OG on ARID1A in clinical samples may provide novel insight into the etiology of IC and identify metabolites that can serve as IC biomarkers for clinical application.”

 

Source: Shahid M et. al. (March 2018). Alpha-oxoglutarate inhibits the proliferation of immortalized normal bladder epithelial cells via an epigenetic switch involving ARID1A. Sci Rep. 8(1):4505.

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