Epigenetics Abstracts 2

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Epigenetic Regulation by Sulforaphane: Opportunities for Breast and Prostate Cancer Chemoprevention.
            (Atwell et al., 2015) Download
Sulforaphane (SFN) is a phytochemical derived from cruciferous vegetables that has multiple molecular targets and anti-cancer properties. Researchers have demonstrated several chemopreventive benefits of SFN consumption, such as reductions in tumor growth, increases in cancer cell apoptosis, and disruption of signaling within tumor microenvironments both in vitro and in vivo. Emerging evidence indicates that SFN exerts several of its chemopreventive effects by altering epigenetic mechanisms. This review summarizes evidence of the impact of SFN on epigenetic events and how they relate to the chemopreventive effects of SFN observed in preclinical and clinical studies of breast and prostate cancers. Specific areas of focus include the role of SFN in the regulation of cell cycle, apoptosis, inflammation, antioxidant defense, and cancer cell signaling and their relationships to epigenetic mechanisms. Finally, remaining challenges and research needs for translating mechanistic work with SFN into human studies and clinical intervention trials are discussed.

Epigenetic predictor of age.
            (Bocklandt et al., 2011) Download
From the moment of conception, we begin to age. A decay of cellular structures, gene regulation, and DNA sequence ages cells and organisms. DNA methylation patterns change with increasing age and contribute to age related disease. Here we identify 88 sites in or near 80 genes for which the degree of cytosine methylation is significantly correlated with age in saliva of 34 male identical twin pairs between 21 and 55 years of age. Furthermore, we validated sites in the promoters of three genes and replicated our results in a general population sample of 31 males and 29 females between 18 and 70 years of age. The methylation of three sites--in the promoters of the EDARADD, TOM1L1, and NPTX2 genes--is linear with age over a range of five decades. Using just two cytosines from these loci, we built a regression model that explained 73% of the variance in age, and is able to predict the age of an individual with an average accuracy of 5.2 years. In forensic science, such a model could estimate the age of a person, based on a biological sample alone. Furthermore, a measurement of relevant sites in the genome could be a tool in routine medical screening to predict the risk of age-related diseases and to tailor interventions based on the epigenetic bio-age instead of the chronological age.

Epigenetic regulation of sensory neurogenesis in the dorsal root ganglion cell line ND7 by folic acid.
            (Boshnjaku et al., 2011) Download
The epigenetic mechanism of folic acid (FA) action on dorsal root ganglion (DRG) cell proliferation and sensory neuron differentiation is not well understood. In this study, the ND7 cell line, derived from DRG cells, was used to elucidate this mechanism. In ND7 cells differentiated with dbcAMP and NGF, Hes1 and Pax3 levels decreased, whereas Neurog2 levels showed a modest increase. Chromatin immunoprecipitation (ChIP) assays examining epigenetic marks at the Hes1 promoter showed that FA favored increased H3K9 and H3K19 acetylation and decreased H3K27 methylation. Hence, FA plays a positive role in cell proliferation. In differentiated ND7 cells, H3K27 methylation decreased, whereas H3K9 and H3K18 acetylation increased at the Neurog2 promoter. FA did not favor this phenotypic outcome. Additionally, in differentiated ND7 Neurog2 associated with the NeuroD1 promoter, FA decreased this association. The results suggest that the switch from proliferation to sensory neuron differentiation in DRG cells is regulated by alterations in epigenetic marks, H3K9/18 acetylation and H3K27 methylation, at Hes1 and Neurog2 promoters, as well as by Neurog2 association with NeuroD1 promoter. FA although positive for proliferation, does not appear to play a role in differentiation.

The epigenetic role of vitamin C in health and disease.
            (Camarena and Wang, 2016) Download
Recent advances have uncovered a previously unknown function of vitamin C in epigenetic regulation. Vitamin C exists predominantly as an ascorbate anion under physiological pH conditions. Ascorbate was discovered as a cofactor for methylcytosine dioxygenases that are responsible for DNA demethylation, and also as a likely cofactor for some JmjC domain-containing histone demethylases that catalyze histone demethylation. Variation in ascorbate bioavailability thus can influence the demethylation of both DNA and histone, further leading to different phenotypic presentations. Ascorbate deficiency can be presented systematically, spatially and temporally in different tissues at the different stages of development and aging. Here, we review how ascorbate deficiency could potentially be involved in embryonic and postnatal development, and plays a role in various diseases such as neurodegeneration and cancer through epigenetic dysregulation.


Epigenetic control of 11 beta-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension.
            (Friso et al., 2008) Download
BACKGROUND:  Lower activity of 11 beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) classically induces hypertension by leading to an altered tetrahydrocortisol- versus tetrahydrocortisone-metabolites (THFs/THE) shuttle. Recent cell culture and animal studies suggest a role for promoter methylation, a major epigenetic feature of DNA, in regulation of HSD11B2 expression. Little is known, however, of human HSD11B2 epigenetic control and its relationship with the onset of hypertension. OBJECTIVE:  To explore the possible relevance of HSD11B2 promoter methylation, by examining human peripheral blood mononuclear cell (PBMC) DNA and urinary THFs/THE ratio as a biochemical indicator of 11beta-HSD2 activity, in blood pressure control. METHODS:  Twenty-five essential hypertensives and 32 subjects on prednisone therapy were analyzed, the latter to investigate 11beta-HSD2 function in the development of hypertension. RESULTS:  Elevated HSD11B2 promoter methylation was associated with hypertension developing in glucocorticoid-treated patients in parallel with a higher urinary THFs/THE ratio. Essential hypertensives with elevated urinary THFs/THE ratio also showed higher HSD11B2 promoter methylation. CONCLUSIONS:  These results show a clear link between the epigenetic regulation through repression of HSD11B2 in PBMC DNA and hypertension.

Maintenance of glutathione levels and its importance in epigenetic regulation.
            (García-Giménez and Pallardó, 2014) Download
Over recent years, growing evidence has suggested a link between GSH metabolism and the control of epigenetic mechanisms.

Role of melatonin in the epigenetic regulation of breast cancer.
            (Korkmaz et al., 2009) Download
The oncostatic properties of melatonin as they directly or indirectly involve epigenetic mechanisms of cancer are reviewed with a special focus on breast cancer. Five lines of evidence suggest that melatonin works via epigenetic processes: (1) melatonin influences transcriptional activity of nuclear receptors (ERalpha, GR and RAR) involved in the regulation of breast cancer cell growth; (2) melatonin down-regulates the expression of genes responsible for the local synthesis or activation of estrogens including aromatase, an effect which may be mediated by methylation of the CYP19 gene or deacetylation of CYP19 histones; (3) melatonin inhibits telomerase activity and expression induced by either natural estrogens or xenoestrogens; (4) melatonin modulates the cell cycle through the inhibition of cyclin D1 expression; (5) melatonin influences circadian rhythm disturbances dependent on alterations of the light/dark cycle (i.e., light at night) with the subsequent deregulation of PER2 which acts as a tumor suppressor gene.

Epigenetic changes in childhood asthma.
            (Kumar et al., 2009) Download
Childhood asthma is linked strongly to atopy and is characterised by a T helper 2 (Th2)-polarised immunological response. Epidemiological studies implicate severe lower respiratory tract viral infections, especially in early childhood, and repeated inhalational exposure to allergens as important synergistic factors in the development of asthma. The way in which these and other environmental factors induce stable alterations in phenotype is poorly understood, but may be explained on the basis of epigenetic changes, which are now recognised to underlie the establishment and maintenance of a Th2 response. Furthermore, ongoing asthmatic inflammation of the airways may be driven by alterations in the expression profile of regulatory microRNA genes, to which epigenetic mechanisms may also contribute. Thus, an understanding of epigenetic mechanisms in asthma has the potential to reveal new approaches for primary prevention or therapeutic intervention in childhood asthma.

Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells.
            (Papoutsis et al., 2010) Download
The BRCA-1 protein is a tumor suppressor involved in repair of DNA damage. Epigenetic mechanisms contribute to its reduced expression in sporadic breast tumors. Through diet, humans are exposed to a complex mixture of xenobiotics and natural ligands of the aromatic hydrocarbon receptor (AhR), which contributes to the etiology of various types of cancers. The AhR binds xenobiotics, endogenous ligands, and many natural dietary bioactive compounds, including the phytoalexin resveratrol (Res). In estrogen receptor- alpha (ER alpha )-positive and BRCA-1 wild-type MCF-7 breast cancer cells, we investigated the influence of AhR activation with the agonist 2,3,7,8 tetrachlorobenzo(p)dioxin (TCDD) on epigenetic regulation of the BRCA-1 gene and the preventative effects of Res. We report that activation and recruitment of the AhR to the BRCA-1 promoter hampers 17 beta -estradiol (E2)-dependent stimulation of BRCA-1 transcription and protein levels. These inhibitory effects are paralleled by reduced occupancy of ER alpha , acetylated histone (AcH)-4, and AcH3K9. Conversely, the treatment with TCDD increases the association of mono-methylated-H3K9, DNA-methyltransferase-1 (DNMT1), and methyl-binding domain protein-2 with the BRCA-1 promoter and stimulates the accumulation of DNA strand breaks. The AhR-dependent repression of BRCA-1 expression is reversed by small interference for the AhR and DNMT1 or pretreatment with Res, which reduces TCDD-induced DNA strand breaks. These results support the hypothesis that epigenetic silencing of the BRCA-1 gene by the AhR is preventable with Res and provide the molecular basis for the development of dietary strategies based on natural AhR antagonists.

Genetic, epigenetic and posttranslational mechanisms of aging.
            (Robert et al., 2010) Download
Gerontological experimentation is and was always strongly influenced by "theories". The early decades of molecular genetics inspired deterministic thinking, based on the "Central Dogma" (DNA --> RNA --> Proteins). With the progress of detailed knowledge of gene-function a much more complicated picture emerged. Regulation of gene-expression turned out to be a highly complicated process. Experimental gerontology produced over the last decades several "paradigms" incompatible with simple genetic determinism. The increasing number of such detailed experimental "facts" revealed the importance of epigenetic factors and of posttranslational modifications in the age-dependent decline of physiological functions. We shall present in this review a short but critical analysis of genetic and epigenetic processes applied to the interpretation of the more and more precisely elucidated experimental paradigms of aging followed by some of the most relevant aging-mechanisms at the post-translational level, the posttranslational modifications of proteins such as the Maillard reaction, the proteolytic production of harmful peptides and the molecular mechanisms of the aging of elastin with the role of the age-dependent uncoupling of the elastin receptor, as well as the loss of several other receptors. We insist also on the well documented influence of posttranslational modifications on gene expression and on the role of non-coding RNA-s. Altogether, these data replace the previous simplistic concepts on gene action as related to aging by a much more complicated picture, where epigenetic and posttranslational processes together with environmentally influenced genetic pathways play key-roles in aging and strongly influence gene expression.

Western herbal medicine, epigenetics, and endometriosis.
            (Stephens et al., 2013) Download
Endometriosis is an enigmatic disease characterized by the presence and growth of endometrial-like tissue outside the uterine cavity. The etiology of endometriosis is poorly understood, yet recent evidence suggests that epigenetic aberrations and heritable changes in the genome may be the key to understanding how to approach this disease. Difficulty in long-term management of endometriosis symptoms and unpredictability of treatment outcome necessitate research into other treatment modalities, such as Western herbal medicine. This article reviews commonly used herbs in the treatment of endometriosis, the effects of phytochemical constituents on endometrial cells, and the impact on the epigenome.

Age-associated epigenetic drift: implications, and a case of epigenetic thrift
            (Teschendorff et al., 2013) Download
It is now well established that the genomic landscape of DNA methylation (DNAm) gets altered as a function of age, a process we here call 'epigenetic drift'. The biological, functional, clinical and evolutionary significance of this epigenetic drift, however, remains unclear. We here provide a brief review of epigenetic drift, focusing on the potential implications for ageing, stem cell biology and disease risk prediction. It has been demonstrated that epigenetic drift affects most of the genome, suggesting a global deregulation of DNAm patterns with age. A component of this drift is tissue-specific, allowing remarkably accurate age-predictive models to be constructed. Another component is tissue-independent, targeting stem cell differentiation pathways and affecting stem cells, which may explain the observed decline of stem cell function with age. Age-associated increases in DNAm target developmental genes, overlapping those associated with environmental disease risk factors and with disease itself, notably cancer. In particular, cancers and precursor cancer lesions exhibit aggravated age DNAm signatures. Epigenetic drift is also influenced by genetic factors. Thus, drift emerges as a promising biomarker for premature or biological ageing, and could potentially be used in geriatrics for disease risk prediction. Finally, we propose, in the context of human evolution, that epigenetic drift may represent a case of epigenetic thrift, or bet-hedging. In summary, this review demonstrates the growing importance of the 'ageing epigenome', with potentially far-reaching implications for understanding the effect of age on stem cell function and differentiation, as well as for disease prevention.

Genetics and epigenetics of rheumatoid arthritis.
            (Viatte et al., 2013) Download
Investigators have made key advances in rheumatoid arthritis (RA) genetics in the past 10 years. Although genetic studies have had limited influence on clinical practice and drug discovery, they are currently generating testable hypotheses to explain disease pathogenesis. Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. Understanding how genetic variants translate into pathogenic mechanisms and ultimately into phenotypes remains a mystery for most of the polymorphisms that confer susceptibility to RA, but functional data are emerging. Interplay between environmental and genetic factors is poorly understood and in need of further investigation. Secondly, we review current knowledge of the role of epigenetics in RA susceptibility. Differences in the epigenome could represent one of the ways in which environmental exposures translate into phenotypic outcomes. The best understood epigenetic phenomena include post-translational histone modifications and DNA methylation events, both of which have critical roles in gene regulation. Epigenetic studies in RA represent a new area of research with the potential to answer unsolved questions.

Oxidative Stress, Undermethylation, and Epigenetics - The Bermuda Triangle of Autism
         Walsh 2010 Download

Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension.
            (Williams et al., 2012) Download           
BACKGROUND:  Hypertension (HTN) represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone-modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP). METHODS:  Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type (WT) and LSD-1 heterozygote knockout (LSD-1(+/-)) mice. Clinical relevance was tested by multivariate associations between single-nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American). RESULTS:  LSD-1 expression was modified by dietary salt in WT mice with lower levels associated with liberal salt intake. LSD-1(+/-) mice expressed lower LSD-1 protein levels than WT mice in kidney tissue. Similar to LSD-1(+/-) mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP (SBP) in response to change from low to liberal salt diet (rs671357, P = 0.01; rs587168, P = 0.005). This association was replicated in the Hispanic (rs587168, P = 0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1(+/-) mice, decreased α-EnaC expression in LSD-1(+/-) mice, and impaired renovascular responsiveness to salt loading in minor allele carriers. CONCLUSION:  The results of this translational research study support a role for LSD-1 in the pathogenesis of salt-sensitive HTN.


 

References

Kumar, RK, MP Hitchins, and PS Foster (2009), ‘Epigenetic changes in childhood asthma.’, Dis Model Mech, 2 (11-12), 549-53. PubMed: 19892885
Atwell, LL, et al. (2015), ‘Epigenetic Regulation by Sulforaphane: Opportunities for Breast and Prostate Cancer Chemoprevention.’, Curr Pharmacol Rep, 1 (2), 102-11. PubMed: 26042194
Bocklandt, S, et al. (2011), ‘Epigenetic predictor of age.’, PLoS One, 6 e14821. PubMed: 21731603
Boshnjaku, V, et al. (2011), ‘Epigenetic regulation of sensory neurogenesis in the dorsal root ganglion cell line ND7 by folic acid.’, Epigenetics, 6 (10), 1207-16. PubMed: 21931278
Camarena, V and G Wang (2016), ‘The epigenetic role of vitamin C in health and disease.’, Cell Mol Life Sci, PubMed: 26846695
Friso, S, et al. (2008), ‘Epigenetic control of 11 beta-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension.’, Atherosclerosis, 199 (2), 323-27. PubMed: 18178212
García-Giménez, JL and FV Pallardó (2014), ‘Maintenance of glutathione levels and its importance in epigenetic regulation.’, Front Pharmacol, 5 88. PubMed: 24847264
Korkmaz, A, et al. (2009), ‘Role of melatonin in the epigenetic regulation of breast cancer.’, Breast Cancer Res Treat, 115 (1), 13-27. PubMed: 18592373
Papoutsis, AJ, et al. (2010), ‘Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells.’, J Nutr, 140 (9), 1607-14. PubMed: 20631324
Robert, L, J Labat-Robert, and AM Robert (2010), ‘Genetic, epigenetic and posttranslational mechanisms of aging.’, Biogerontology, 11 (4), 387-99. PubMed: 20157779
Stephens, L, J Whitehouse, and M Polley (2013), ‘Western herbal medicine, epigenetics, and endometriosis.’, J Altern Complement Med, 19 (11), 853-59. PubMed: 23738681
Teschendorff, AE, J West, and S Beck (2013), ‘Age-associated epigenetic drift: implications, and a case of epigenetic thrift’, Hum Mol Genet, 22 (R1), R7-R15. PubMed: 23918660
Viatte, S, D Plant, and S Raychaudhuri (2013), ‘Genetics and epigenetics of rheumatoid arthritis.’, Nat Rev Rheumatol, 9 (3), 141-53. PubMed: 23381558
Williams, JS, et al. (2012), ‘Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension.’, Am J Hypertens, 25 (7), 812-17. PubMed: 22534796