Alpha-oxoglutarate inhibits the proliferation of immortalized normal bladder epithelial cells via an epigenetic switch involving ARID1A.
Muhammad ShahidNicole GullAustin YeonEunho ChoJooeun BaeHyun Seok YoonSungyong YouHana YoonMinjung KimBenjamin P BermanJayoung KimPublished in: Scientific reports (2018)
Interstitial cystitis (IC) is a chronic urinary tract disease that is characterized by unpleasant sensations, such as persistent pelvic pain, in the absence of infection or other identifiable causes. We previously performed comprehensive metabolomics profiling of urine samples from IC patients using nuclear magnetic resonance and gas-chromatography/mass spectrometry and found that urinary α-oxoglutarate (α-OG), was significantly elevated. α-OG, a tricarboxylic acid (TCA) cycle intermediate, reportedly functions to suppress the proliferation of immortalized normal human bladder epithelial cells. Here, we identified AT-rich interactive domain 1 A (ARID1A), a key chromatin remodeler, as being hypomethylated and upregulated by α-OG treatment. This was done through EPIC DNA methylation profiling and subsequent biochemical approaches, including quantitative RT-PCR and western blot analyses. Furthermore, we found that α-OG almost completely suppresses ten-eleven translocation (TET) activity, but does not affect DNA methyltransferase (DNMT) activity. Altogether, our studies reveal the potential role of α-OG in epigenetic remodeling through its effects on ARID1A and TET expression in the bladder. This may provide a new possible therapeutic strategy in treating IC.
Keyphrases
- dna methylation
- urinary tract
- genome wide
- gene expression
- gas chromatography mass spectrometry
- magnetic resonance
- signaling pathway
- spinal cord injury
- end stage renal disease
- single cell
- ejection fraction
- chronic kidney disease
- poor prognosis
- newly diagnosed
- chronic pain
- mass spectrometry
- peritoneal dialysis
- endothelial cells
- south africa
- dna damage
- high resolution
- prognostic factors
- neuropathic pain
- cell free
- pain management
- magnetic resonance imaging
- rectal cancer
- circulating tumor
- patient reported outcomes
- solid phase extraction
- induced pluripotent stem cells
- pluripotent stem cells
- oxidative stress
- single molecule
- binding protein
- human health
- gas chromatography
- postoperative pain
- combination therapy