Subtle Alterations in DNA Methylation Patterns in Normal Cells in Response to Dietary Stilbenoids

Beetch, Megan; Lubecka, Katarzyna; Kristofzski, Heather; Suderman, Matthew; Stefańska, Barbara

doi:10.1002/mnfr.201800193

Cited by 8 publications

(11 citation statements)

References 54 publications

(143 reference statements)

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“…Another possibility is that RSV regulates ASPA through a methylation mechanism. RSV has previously been shown to change the methylation pattern of specific genes [78,79]. Moreover, distinct patterns of CpG methylation are related to ageing, and in particular, the CpG methylation status of ASPA appears to be a hallmark of ageing.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Dembić

Andersen

Bastin

et al. 2019

Molecular Genetics and Metabolism

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Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mitochondrial function, and more recently it was shown to restore fatty acid βoxidation (FAO) capacities in patient fibroblasts harboring mutations with residual enzyme activity. Many of RSV's beneficial effects are mediated by the transcriptional coactivator PGC-1α, a direct target of SIRT1 and a master regulator of the mitochondrial fatty acid oxidation. Despite numerous studies RSV's mechanism of action is still not completely elucidated. Our aim was to investigate the effects of RSV on gene regulation on a wide scale, possibly to detect novel genes whose upregulation by RSV may be of interest with respect to disease treatment. We performed Next Generation Sequencing of RNA on normal fibroblasts treated with RSV. To investigate whether the effects of RSV are mediated through SIRT1 we expanded the analysis to include SIRT1knockdown fibroblasts. We identified the aspartoacylase (ASPA) gene, mutated in Canavan disease, to be strongly up-regulated by RSV in several cell lines, including Canavan disease fibroblasts. We further link RSV to the up-regulation of other genes involved in myelination including the glial specific transcription factors POU3F1, POU3F2, and myelin basic protein (MBP). We also observe a strong up-regulation by RSV of the riboflavin transporter gene SLC52a1. Mutations in SLC52a1 cause transient multiple acyl-CoA dehydrogenase deficiency (MADD). Our analysis of alternative splicing identified novel metabolically important genes affected by RSV, among which is particularly interesting the α subunit of the stimulatory G protein (Gsα), which regulates the cellular levels of cAMP through adenylyl cyclase. We conclude that in fibroblasts RSV stimulates the PGC-1α and p53 pathways, and up-regulates genes affecting the glucose metabolism, mitochondrial β-oxidation, and mitochondrial biogenesis. We further confirm that RSV might be a relevant treatment in the correction of FAO deficiencies and we suggest that treatment in other metabolic disorders including Canavan disease and MADD might be also beneficial.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Dembić

Andersen

Bastin

et al. 2019

Molecular Genetics and Metabolism

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“…Global hypomethylation also contributes to multi-step carcinogenesis by activating transcription of repetitive sequences and transposable elements, which consequently contributes to genome rearrangements and chromosomal instability in cancer, including breast cancer 27 . Additionally, loci-specific hypomethylation can lead to the activation of oncogenes and pro-metastatic genes [28][29][30][31] .…”

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confidence: 99%

DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer

Beetch

Harandi-Zadeh

Yang

et al. 2020

Sci Rep

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triple-negative breast cancer (tnBc) is a subtype of breast cancer unresponsive to traditional receptortargeted treatments, leading to a disproportionate number of deaths. invasive breast cancer is believed to evolve from non-invasive ductal carcinoma in situ (DciS). Detection of triple-negative DciS (tn-DciS) is challenging, therefore strategies to study molecular events governing progression of pre-invasive tn-DciS to invasive tnBc are needed. Here, we study a canine tn-DciS progression and investigate the DnA methylation landscape of normal breast tissue, atypical ductal hyperplasia (ADH), DciS and invasive breast cancer. We report hypo-and hypermethylation of genes within functional categories related to cancer such as transcriptional regulation, apoptosis, signal transduction, and cell migration. DnA methylation changes associated with cancer-related genes become more pronounced at invasive breast cancer stage. Importantly, we identify invasive-only and DCIS-specific DNA methylation alterations that could potentially determine which lesions progress to invasive cancer and which could remain as pre-invasive DciS. changes in DnA methylation during tn-DciS progression in this canine model correspond with gene expression patterns in human breast tissues. this study provides evidence for utilizing methylation status of gene candidates to define late-stage (DCIS and invasive), invasive stage only or DciS stage only of tn-DciS progression. Breast cancer is classified into subtypes based on the expression of growth factor receptors including the estrogen receptor (ER), the progesterone receptor (PR), and the receptor for human epidermal growth factor (HER-2) 1. Growth of breast tumors expressing any of these receptors may be controlled effectively by treatment in the adjuvant setting with receptor-targeted drugs 2. However, breast tumors that do not express any of these receptors have no known effective adjuvant treatment capable of controlling tumor growth. Such tumors are referred to as triple-negative breast cancers (TNBC) and are the most aggressive and lethal of all breast malignancies 2. TNBC accounts for 15% of breast cancer cases and a disproportionate percentage of breast cancer deaths among women 3. It has been shown that patients with TNBC have poor prognosis and shorter median time to relapse compared to patients with other subtypes of breast cancer 4. Ductal carcinoma in situ (DCIS) is defined as a non-invasive overgrowth of cells characterized by high proliferation within the breast ductal system. Studies suggest that triple-negative DCIS (TN-DCIS), a rare type of DCIS, is a precursor stage of invasive breast cancer 5,6. Therefore, early detection of TN-DCIS is important in preventing breast cancer cases that may progress to triple negative invasive carcinoma. However, TN-DCIS is challenging to detect at early stage in humans 7. Despite efforts to use immunohistochemistry to measure receptor expression in scientific studies of human DCIS tissues, detection of receptor status, including ER, is not routi...

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“…Interestingly, a genomewide DNA methylation study in colorectal cancer cells exposed to curcumin shows that curcumin caused loci-specific both hypermethylation and hypomethylation, predominantly in partially methylated CpG sites (Link et al, 2013). Thus, curcumin effects on the DNA methylation patterns are differential and likely depend of CpG location and gene function as suggested for stilbenoids (Beetch et al, 2018;Lubecka et al, 2016).…”

Section: A Link Between Antioxidant Properties Of Genistein and Genmentioning

confidence: 99%

“…Stilbenoid compounds such as resveratrol and pterostilbene alter DNA methylation patterns at gene‐specific loci (Beetch, Lubecka, Kristofzski, Suderman, & Stefanska, ; Kala & Tollefsbol, ; Lubecka et al, ; Medina‐Aguilar et al, ; Papoutsis, Lamore, Wondrak, Selmin, & Romagnolo, ; Stefanska et al, ; Stefanska et al, ). Our group (Beetch et al, ; Beetch et al, ; Lubecka et al, ) and others (Medina‐Aguilar et al, ) using genome‐wide technologies have demonstrated that stilbenoids remodel patterns of DNA methylation in human cells, including cancer and normal cells, leading to CpG‐loci specific hypermethylation or hypomethylation. In cancer cells, CpG sites, which were hypomethylated in response to stilbenoids, are associated with genes falling into a category of tumour suppressor genes, whereas genes containing hypermethylated CpG sites upon exposure to stilbenoids are enriched with oncogenic and pro‐metastatic functions.…”

Section: Interrelationship Between Antioxidant Properties and Dna Metmentioning

confidence: 99%

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Dietary antioxidants remodel DNA methylation patterns in chronic disease

Beetch

Harandi-Zadeh

Shen

et al. 2019

British J Pharmacology

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Chronic diseases account for over 60% of all deaths worldwide according to the World Health Organization reports. Majority of cases are triggered by environmental exposures that lead to aberrant changes in the epigenome, specifically, the DNA methylation patterns. These changes result in altered expression of gene networks and activity of signalling pathways. Dietary antioxidants, including catechins, flavonoids, anthocyanins, stilbenes and carotenoids, demonstrate benefits in the prevention and/or support of therapy in chronic diseases. This review provides a comprehensive discussion of potential epigenetic mechanisms of antioxidant compounds in reversing altered patterns of DNA methylation in chronic disease. Antioxidants remodel the DNA methylation patterns through multiple mechanisms, including regulation of epigenetic enzymes and chromatin remodelling complexes. These effects can further contribute to antioxidant properties of the compounds. On the other hand, decrease in oxidative stress itself can impact DNA methylation delivering additional link between antioxidant mechanisms and epigenetic effects of the compounds. Linked Articles This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc

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Subtle Alterations in DNA Methylation Patterns in Normal Cells in Response to Dietary Stilbenoids

Abstract: The study provides strong support for testing the utility of polyphenol-mediated changes in DNA methylation as quantitative measures of long-term dietary exposures in nutritional epidemiology and clinical trials.

Cited by 8 publications

References 54 publications

Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer

Dietary antioxidants remodel DNA methylation patterns in chronic disease

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