Extensive Inter-Cyst DNA Methylation Variation in Autosomal Dominant Polycystic Kidney Disease Revealed by Genome Scale Sequencing

Bowden, Sarah A.; Stockwell, Peter A.; Rodger, Euan J.; Parry, Matthew; Eccles, Michael R.; Stayner, Cherie; Chatterjee, Aniruddha

doi:10.3389/fgene.2020.00348

Cited by 14 publications

(9 citation statements)

References 43 publications

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“…For the analysis of RRBS methylomes, we have employed a MspI fragment-based analysis approach. The fragment-based analysis approach for RRBS has been well described previously [ 30 , 31 , 74 , 75 ]. We restricted our analysis to fragments with at least two CpG sites covered by 10 or more sequenced reads.…”

Section: Methodsmentioning

confidence: 99%

Comparison of Global DNA Methylation Patterns in Human Melanoma Tissues and Their Derivative Cell Lines

Rodger

Almomani

Ludgate

et al. 2021

Cancers

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DNA methylation is a heritable epigenetic mark that is fundamental to mammalian development. Aberrant DNA methylation is an epigenetic hallmark of cancer cells. Cell lines are a critical in vitro model and very widely used to unravel mechanisms of cancer cell biology. However, limited data are available to assess whether DNA methylation patterns in tissues are retained when cell lines are established. Here, we provide the first genome-scale sequencing-based methylation map of metastatic melanoma tumour tissues and their derivative cell lines. We show that DNA methylation profiles are globally conserved in vitro compared to the tumour tissue of origin. However, we identify sites that are consistently hypermethylated in cell lines compared to their tumour tissue of origin. The genes associated with these common differentially methylated regions are involved in cell metabolism, cell cycle and apoptosis and are also strongly enriched for the H3K27me3 histone mark and PRC2 complex-related genes. Our data indicate that although global methylation patterns are similar between tissues and cell lines, there are site-specific epigenomic differences that could potentially impact gene expression. Our work provides a valuable resource for identifying false positives due to cell culture and for better interpretation of cancer epigenetics studies in the future.

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Section: Methodsmentioning

confidence: 99%

Comparison of Global DNA Methylation Patterns in Human Melanoma Tissues and Their Derivative Cell Lines

Rodger

Almomani

Ludgate

et al. 2021

Cancers

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“…Fourth, analyzing global methylation patterns of individual cysts derived from the same ADPKD patient ( Table 1 ) revealed that approximately 15% of analyzed fragments exhibited inter-cyst variation in DNA methylation pattern. While the CpG islands and gene body regions demonstrated elevated levels of methylation variation, the intergenic regions had comparatively stable methylation levels within cysts from the same ADPKD patient ( Bowden et al, 2020 ).…”

Section: The Roles and Mechanisms Of Epigenetic Regulation In Adpkdmentioning

confidence: 99%

“…These studies provided new molecular mechanisms of the disease and provided a novel target for therapeutic purposes. With the advancements made in technology, the field has witnessed an exponential burst in studies aimed at characterizing the epigenome of ADPKD kidneys ( Woo et al, 2014 ; Woo et al, 2015 ; Bowden et al, 2018 ; Bowden et al, 2020 ). These studies have shed light on the role of DNA methylation in the pathogenesis of ADPKD.…”

Section: The Roles and Mechanisms Of Epigenetic Regulation In Adpkdmentioning

confidence: 99%

Molecular Mechanisms of Epigenetic Regulation, Inflammation, and Cell Death in ADPKD

Agborbesong

et al. 2022

Front. Mol. Biosci.

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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder, which is caused by mutations in thePKD1andPKD2genes, characterizing by progressive growth of multiple cysts in the kidneys, eventually leading to end-stage kidney disease (ESKD) and requiring renal replacement therapy. In addition, studies indicate that disease progression is as a result of a combination of factors. Understanding the molecular mechanisms, therefore, should facilitate the development of precise therapeutic strategies for ADPKD treatment. The roles of epigenetic modulation, interstitial inflammation, and regulated cell death have recently become the focuses in ADPKD. Different epigenetic regulators, and the presence of inflammatory markers detectable even before cyst growth, have been linked to cyst progression. Moreover, the infiltration of inflammatory cells, such as macrophages and T cells, have been associated with cyst growth and deteriorating renal function in humans and PKD animal models. There is evidence supporting a direct role of the PKD gene mutations to the regulation of epigenetic mechanisms and inflammatory response in ADPKD. In addition, the role of regulated cell death, including apoptosis, autophagy and ferroptosis, have been investigated in ADPKD. However, there is no consensus whether cell death promotes or delays cyst growth in ADPKD. It is therefore necessary to develop an interactive picture between PKD gene mutations, the epigenome, inflammation, and cell death to understand why inherited PKD gene mutations in patients may result in the dysregulation of these processes that increase the progression of renal cyst formation.

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“…The hypermethylation was identified with 3′ end of PKD1 gene body, but not associated with decreased expression of PKD1 mRNA. A recent study investigated the DNA methylation changes of cystic epithelia within independent cysts by RRBS (Bowden et al, 2020). This study demonstrated that the greatest amount of variation occurs in fragments within CpG islands and gene bodies, but not within intergenic fragments across the ADPKD kidney.…”

Section: Dna Methylationmentioning

confidence: 99%

Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling

Zhou

Torres

2022

Front. Mol. Biosci.

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Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes shared by many other diseases. Dysfunction of the polycystins, encoded by the PKD genes, is closely associated with disruption of calcium and upregulation of cyclic AMP and protein kinase A (PKA) signaling, affecting most downstream regulatory, signaling, and pathophysiologic pathways altered in this disease. Interventions acting on G protein coupled receptors to inhibit of 3′,5′-cyclic adenosine monophosphate (cAMP) production have been effective in preclinical trials and have led to the first approved treatment for ADPKD. However, completely blocking cAMP mediated PKA activation is not feasible and PKA activation independently from cAMP can also occur in ADPKD. Therefore, targeting the cAMP/PKA/CREB pathway beyond cAMP production makes sense. Redundancy of mechanisms, numerous positive and negative feedback loops, and possibly counteracting effects may limit the effectiveness of targeting downstream pathways. Nevertheless, interventions targeting important regulatory, signaling and pathophysiologic pathways downstream from cAMP/PKA activation may provide additive or synergistic value and build on a strategy that has already had success. The purpose of this manuscript is to review the role of cAMP and PKA signaling and their multiple downstream pathways as potential targets for emergent therapies for ADPKD.

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Extensive Inter-Cyst DNA Methylation Variation in Autosomal Dominant Polycystic Kidney Disease Revealed by Genome Scale Sequencing

Cited by 14 publications

References 43 publications

Comparison of Global DNA Methylation Patterns in Human Melanoma Tissues and Their Derivative Cell Lines

Comparison of Global DNA Methylation Patterns in Human Melanoma Tissues and Their Derivative Cell Lines

Molecular Mechanisms of Epigenetic Regulation, Inflammation, and Cell Death in ADPKD

Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling

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