Epigenetics in ADPKD: Understanding Mechanisms and Discovering Treatment
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ABSTRACT
Epigenetics is the study of all heritable changes in gene expression and chromatin organization that are caused by mechanisms independent of the DNA sequence itself. Similar to the genetic information found within the sequence of DNA, epigenetic information can also be inherited across generations. Epigenetic gene regulation includes, but is not limited to, DNA methylation and histone modification through acetylation, methylation, ubiquitylation, phosphorylation, or sumoylation. The roles of epigenetic modulation on gene expression and protein function have recently become the focus in autosomal dominant polycystic kidney disease (ADPKD). An interactive picture between PKD gene mutations and the epigenome needs to be developed to understand why inherited PKD gene mutations in patients may result in epigenetic changes that increase the progression of renal cyst formation. Recent studies demonstrate that PKD1 mutation increases the expression of epigenetic regulators, including DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs) and bromodomain proteins. Conversely, inhibition of epigenetic regulators delays cyst growth in Pkd1 knockout mouse models, supporting the importance of abnormal epigenetic regulation in ADPKD. One of the exciting findings is that targeting Sirt1, a class III HDAC, with nicotinamide (vitamin B3) delays renal cyst growth and preserves renal function in three Pkd1 knockout animal models. The hypermethylation of PKD1 gene in gene-body regions implicates that DNA methylation-mediated epigenetic silencing of PKD genes is also a potential mechanism underlying cystogenesis. In this chapter, we will summarize the current knowledge on the role of epigenetics in ADPKD and its translational potential to identify much needed new therapies. We will also discuss the tools to study epigenetic mechanisms in ADPKD and their applications on understanding how epigenetic events intertwine with PKD-associated signaling pathways, including c-Myc, EGFR, HSP90, STAT3/STAT6, AMPK, Wnt/β-catenin, ILK/mTOR, hedgehog, GSK3β and NF-κB/inflammation signaling.
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