Barbara Stefanska
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Epigenetics refers to the molecular events controlling gene expression that are independent of changes in the underlying DNA sequence. These events include DNA methylation, covalent histone modifications, and non-coding RNA-related mechanisms. Epigenetic modifications of DNA, namely DNA methylation, have been shown to contribute to the etiology of chronic diseases with cancer at the forefront. DNA methylation is dynamic and serves as an adaptive mechanism to a wide variety of environmental factors including diet.
My laboratory is focused on addressing the following scientific questions:
1) Do dietary bioactive compounds act through epigenetic mechanisms to prevent cancer and exert beneficial effects in adjuvant therapy?
Our hypothesis is that dietary polyphenols (e.g., resveratrol, pterostilbene, piceatannol, and coffee polyphenols) impact DNA methylation patterns and thereby gene transcription via modulation of expression and activity of epigenetic enzymes such as TETs and DNMTs. Changes in these enzymes, alter the occupancy of specific protein complexes in gene regulatory regions which determines chromatin structure and as a result gene transcription. Through this mode of action, polyphenols reverse cancer-specific patterns of DNA methylation; they lead to the activation of methylation-silenced tumour suppressor genes and concomitant suppression of demethylation-activated oncogenes and prometastatic genes. We are also exploring if epigenetic mechanisms regulated by polyphenols can sensitize cancer cells to traditional anti-cancer therapeutics.
2) Do dietary bioactive compounds reverse epigenetic aberrations underlying initiation of inflammation and inflammation-driven cancer?
Existing evidence suggests that at sites of inflammation the release of reactive oxygen species causes DNA damage that induces re-localization of epigenetic proteins and results in DNA methylation changes of associated genes during tumorigenesis. We hypothesize that bioactive compounds can prevent cancer development by targeting those changes in the DNA methylation patterns.
3) Do changes in epigenetic marks reflect dietary exposure to bioactive compounds?
We hypothesize that exposure to dietary polyphenols may leave stable marks in human body by inducing changes in DNA methylation patterns. Such molecular markers in easily accessible specimens are needed and should reflect long-term exposures. This will deliver quantitative tools for measuring the intake of bioactive food components in clinical and epidemiological studies.
Current Projects:
1) Epigenetic regulation of the NOTCH oncogenic pathway in response to polyphenols from blueberries and grapes (stilbenoids: pterostilbene, piceatannol, resveratrol).
2) Epigenetic mechanisms of polyphenols in prevention of inflammation in a mouse model of colitis and colon cancer.
3) Epigenetic biomarkers of exposure to dietary bioactive compounds.
Please find more information at:
http://epigenetics.wixsite.com/stefanskalab
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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Epigenetics refers to control of gene expression without changes to the underlying DNA sequence. DNA methylation, a dynamic epigenetic modification responsive to environmental factors, underlies genomic instability, silencing of tumor suppressor genes (TSGs), and activation of genes driving cancer development. Reversing DNA methylation patterns established during carcinogenesis constitutes a promising anti-cancer strategy. Interestingly, certain dietary polyphenols, such as stilbenoids abundantly found in grapes and blueberries, have been shown to exert anti-cancer effects through epigenetic gene regulation. The overarching objective of my research is to understand epigenetic mechanisms of stilbenoids’ anti-cancer effects. We hypothesize that dietary stilbenoids, resveratrol (RSV) and pterostilbene (PTS), modulate DNA methylation patterns and thereby gene transcription via modifying expression and activity of epigenetic enzymes such as DNA methyltransferases (DNMTs) and transcriptional machinery such as transcription factors (TFs). Stilbenoid-induced changes in DNA methylation and transcriptional machinery could, in turn, lead to reactivation of methylation-silenced TSGs and downregulation of epigenetically-activated oncogenes leading to reduced cancer development. Upon treatment with RSV (15 μM, 9 days), DNA methylation levels in MCF10CA1a breast cancer cells were altered as assessed by genome-wide DNA methylation analysis. Hypermethylated CpG sites corresponded to genes predominantly associated with oncogenic functions, whereas hypomethylated sites were located in genes with potential tumor suppressor roles. Changes in methylation and expression of candidate oncogenes and TSGs were examined using pyrosequencing and qPCR, respectively, upon treatment with RSV or PTS. Further, chromatin immunoprecipitation (ChIP) sequencing assessed DNA binding events, including occupancy of DNMTs and TFs at stilbenoid-mediated differentially methylated sites. Specific putative roles for de novo DNMTs in mediating changes in DNA methylation patterns upon exposure to stilbenoids were established. Based on our findings in cell lines, we turned to an in vivo model of methyl donor deficiency to assess the contribution of methyl donors, another important factor for maintaining normal DNA methylation patterns, to carcinogenesis. Collectively, these findings provide evidence that dietary stilbenoids may exert their anti-cancer effects, at least partially, by impacting DNA methylation machinery, and as a result, this line of evidence has potential to be used to develop novel anti-cancer approaches.
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Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
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Epigenetic alterations resulting in a dysregulated transcriptional program of the cell have been previously described in liver cancer. Importantly, certain fruits including grapes and berries contain stilbenoid polyphenols, such as pterostilbene (PTS) and resveratrol (RSV), that have been shown to reverse epigenetic alterations by remodeling DNA methylation patterns. However, the underlying downstream mechanisms of the anticancer actions of PTS and RSV remain unclear. Here, we describe a novel cancer-promoting gene, BRUNOL5, in the hepatocellular carcinoma (HCC) cell line, HepG2, is regulated by PTS/RSV. Using siRNA-mediated knockdown of BRUNOL5 followed by RNA sequencing, we determined 4,406 transcripts with significantly dysregulated expression profiles in response to depletion of BRUNOL5. Many genes with significant downregulation were found to have oncogenic functions, whereas genes with significant upregulation were found to have tumour-suppressive functions. We selected multiple downregulated candidates including TLR4, TIMP3, and MMP2 for further investigation, considering their functions that promote cell proliferation and invasion, migration, and metastasis. Additionally, we observed significant downregulation of genes involved in various oncogenic signaling pathways including Notch, Wnt, TGFB/BMP, and Hhg signaling. We then investigated various candidate upregulated transcripts, including MST1, SLC22A7, and CDHR5, that are involved in promoting apoptosis, increasing chemosensitivity and cell adhesion. Interestingly, depletion of BRUNOL5 mimicked the effects of PTS/RSV treatment of HepG2 cells. PTS/RSV treatment of HepG2 correlated with significant BRUNOL5 promoter hypermethylation, which corresponded with significant decreases of BRUNOL5 at both transcript and protein levels. Interestingly, we observed similar effects of PTS/RSV on the aforementioned oncogenic signaling pathways. Our findings indicate that BRUNOL5 is a novel cancer-promoting gene regulated by stilbenoid polyphenols, and that the pleiotropic anti-cancer effects of PTS/RSV may possibly be mediated, at least partially, through BRUNOL5 epigenetic downregulation. Through RNA immunoprecipitation followed by qPCR, we discovered decreased BRUNOL5 binding to TLR4 and CYR61 transcripts, potentially connecting with a decrease in the level of those transcripts. Our findings describe a novel cancer-promoting gene in HCC that is epigenetically regulated by stilbenoids. We further provide a better understanding of a potential mechanism that may contribute to the anti-cancer action of stilbenoid polyphenols.
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Epigenetic alterations are estimated to be linked to 30% of sporadic breast cancer cases. Interestingly, certain dietary polyphenols, such as pterostilbene found abundantly in blueberries, have been shown to regulate gene expression and reverse tumour development by altering epigenetic patterns. Our group has proposed the involvement of DNA methyltransferase 3B (DNMT3B) and oncogenic transcription factor OCT1 as vital players in polyphenol-mediated targeting of oncogenes. We have also identified enhancers as important regulatory regions with altered DNA methylation in response to polyphenols. However, the genome wide effects of pterostilbene-mediated alterations in the occupancy of DNMT3B and OCT1 in enhancer regions of oncogenes remains to be elucidated.In this study, following chromatin immunoprecipitation (ChIP) sequencing analyses of highly invasive MCF10CA1a breast cancer cells treated with 7μM pterostilbene for 9 days, we discovered that pterostilbene treatment leads to altered occupancy of DNMT3B and OCT1 at enhancer regions of genes with oncogenic functions. In addition, trimethylation at lysine 36 of histone 3 (H3K36me3) enrichment was measured to indicate decrease in gene transcriptional activity. QPCR and pyrosequencing were performed to assess gene expression and DNA methylation of the selected oncogenes, respectively. We identified 20 candidate genes whose enhancers showed increased binding of DNMT3B, decreased occupancy of OCT1 and reduced enrichment of H3K36me3 in MCF10CA1a upon pterostilbene exposure compared with control untreated cells (p
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