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  1. Sirtuins: the future insight
    Suvarna BS
    Kathmandu Univ Med J (KUMJ), 2012 Apr-Jun;10(38):77-82.
    PMID: 23132482
    Sirtuins are evolutionary conserved NAD+ dependent acetyl-lysine deacetylases and ADP ribosyltransferases dual-function enzymes involved in the regulation of metabolism and lifespan. Sirtuins represent a promising new class of III NAD dependent histone deacetylases that regulate a number of physiological processes, originally identified in yeast. Sirtuins regulate various normal and abnormal cellular and metabolic processes, including tumorgenesis, neurodegeneration and processes associated with type 2 diabetes and obesity. Several age-related diseases such as Alzheimer's disease and longevity have also been linked to the functions of sirtuins. Because of these associations, the identification of small molecules sirtuin modulators has been of significant interest.
    Matched MeSH terms: Epigenomics
  2. Epigenetics: The master control of endothelial cell fate in cancer
    V Subramaniam A, Yehya AHS, Cheng WK, Wang X, Oon CE
    Life Sci, 2019 Sep 01;232:116652.
    PMID: 31302197 DOI: 10.1016/j.lfs.2019.116652
    The development of new blood vessels from pre-existing vasculature is called angiogenesis. The growth of tumors depends on a network of supplying vessels that provide them with oxygen and nutrients. Pro-angiogenic factors that are secreted by tumors will trigger the sprouting of nearby existing blood vessels towards themselves and therefore researchers have developed targeted therapy towards these pro-angiogenic proteins to inhibit angiogenesis. However, certain pro-angiogenic proteins tend to bypass the inhibition. Thus, instead of targeting these expressed proteins, research towards angiogenesis inhibition had been focused on a deeper scale, epigenetic modifications. Epigenetic regulatory mechanisms are a heritable change in a sequence of stable but reversible gene function modification yet do not affect the DNA primary sequence directly. Methylation of DNA, modification of histone and silencing of micro-RNA (miRNA)-associated gene are currently considered to initiate and sustain epigenetic changes. Recent findings on the subject matter have provided an insight into the mechanism of epigenetic modifications, thus this review aims to present an update on the latest studies.
    Matched MeSH terms: Epigenomics*
  3. Epigenetic changes and their relationship to somaclonal variation: a need to monitor the micropropagation of plantation crops
    Azizi P, Hanafi MM, Sahebi M, Harikrishna JA, Taheri S, Yassoralipour A, et al.
    Funct Plant Biol, 2020 05;47(6):508-523.
    PMID: 32349860 DOI: 10.1071/FP19077
    Chromatin modulation plays important roles in gene expression regulation and genome activities. In plants, epigenetic changes, including variations in histone modification and DNA methylation, are linked to alterations in gene expression. Despite the significance and potential of in vitro cell and tissue culture systems in fundamental research and marketable applications, these systems threaten the genetic and epigenetic networks of intact plant organs and tissues. Cell and tissue culture applications can lead to DNA variations, methylation alterations, transposon activation, and finally, somaclonal variations. In this review, we discuss the status of the current understanding of epigenomic changes that occur under in vitro conditions in plantation crops, including coconut, oil palm, rubber, cotton, coffee and tea. It is hoped that comprehensive knowledge of the molecular basis of these epigenomic variations will help researchers develop strategies to enhance the totipotent and embryogenic capabilities of tissue culture systems for plantation crops.
    Matched MeSH terms: Epigenomics*
  4. Fulltext Epigenome-wide association study of adiposity and future risk of obesity-related diseases
    Campanella G, Gunter MJ, Polidoro S, Krogh V, Palli D, Panico S, et al.
    Int J Obes (Lond), 2018 Dec;42(12):2022-2035.
    PMID: 29713043 DOI: 10.1038/s41366-018-0064-7
    BACKGROUND: Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.

    METHODS: DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.

    RESULTS: We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10-8 to 3.27×10-18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10-7), higher triglyceride levels (P = 5.37×10-9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10-10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P 

    Matched MeSH terms: Epigenomics/methods*
  5. Eating According to One's Genes? Exploring the French Public's Understanding of and Reactions to Personalized Nutrition
    Fournier T, Poulain JP
    Qual Health Res, 2018 Dec;28(14):2195-2207.
    PMID: 30132729 DOI: 10.1177/1049732318793417
    In this article, we analyze qualitatively the understanding of and reactions to personalized nutrition (PN) among the French public. Focus groups were conducted to identify the opinions and discourses about two applications of knowledge from nutritional (epi)genomics: a biotechnology (nutrigenetic testing) and a public awareness campaign (the "first thousand days of life" initiative). Our objective was to understand to what extent PN could lead to changes in eating practices as well as in the representations of food-health relationships within France, a country characterized by a strong commitment to commensality and a certain "nutritional relativism." Although discourses on nutritional genomics testify to a resistance to food medicalization, nutritional epigenomics appears as more performative because it introduces the question of transgenerational transmission, thus parental responsibility.
    Matched MeSH terms: Epigenomics
  6. Fulltext Ageing, Drosophila melanogaster and Epigenetics
    Halim MA, Tan FHP, Azlan A, Rasyid II, Rosli N, Shamsuddin S, et al.
    Malays J Med Sci, 2020 May;27(3):7-19.
    PMID: 32684802 MyJurnal DOI: 10.21315/mjms2020.27.3.2
    Ageing is a phenomenon where the accumulation of all the stresses that alter the functions of living organisms, halter them from maintaining their physiological balance and eventually lead to death. The emergence of epigenetic tremendously contributed to the knowledge of ageing. Epigenetic changes in cells or tissues like deoxyribonucleic acid (DNA) methylation, modification of histone proteins, transcriptional modification and also the involvement of non-coding DNA has been documented to be associated with ageing. In order to study ageing, scientists have taken advantage of several potential organisms to aid them in their study. Drosophila melanogaster has been an essential model in establishing current understanding of the mechanism of ageing as they possess several advantages over other competitors like having homologues to more than 75% of human disease genes, having 50% of Drosophila genes are homologues to human genes and most importantly they are genetically amenable. Here, we would like to summarise the extant knowledge about ageing and epigenetic process and the role of Drosophila as an ideal model to study epigenetics in association with ageing process.
    Matched MeSH terms: Epigenomics
  7. Fulltext Identification of diagnostic markers in colorectal cancer via integrative epigenomics and genomics data
    Kok-Sin T, Mokhtar NM, Ali Hassan NZ, Sagap I, Mohamed Rose I, Harun R, et al.
    Oncol Rep, 2015 Jul;34(1):22-32.
    PMID: 25997610 DOI: 10.3892/or.2015.3993
    Apart from genetic mutations, epigenetic alteration is a common phenomenon that contributes to neoplastic transformation in colorectal cancer. Transcriptional silencing of tumor-suppressor genes without changes in the DNA sequence is explained by the existence of promoter hypermethylation. To test this hypothesis, we integrated the epigenome and transcriptome data from a similar set of colorectal tissue samples. Methylation profiling was performed using the Illumina InfiniumHumanMethylation27 BeadChip on 55 paired cancer and adjacent normal epithelial cells. Fifteen of the 55 paired tissues were used for gene expression profiling using the Affymetrix GeneChip Human Gene 1.0 ST array. Validation was carried out on 150 colorectal tissues using the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) technique. PCA and supervised hierarchical clustering in the two microarray datasets showed good separation between cancer and normal samples. Significant genes from the two analyses were obtained based on a ≥2-fold change and a false discovery rate (FDR) p-value of <0.05. We identified 1,081 differentially hypermethylated CpG sites and 36 hypomethylated CpG sites. We also found 709 upregulated and 699 downregulated genes from the gene expression profiling. A comparison of the two datasets revealed 32 overlapping genes with 27 being hypermethylated with downregulated expression and 4 hypermethylated with upregulated expression. One gene was found to be hypomethylated and downregulated. The most enriched molecular pathway identified was cell adhesion molecules that involved 4 overlapped genes, JAM2, NCAM1, ITGA8 and CNTN1. In the present study, we successfully identified a group of genes that showed methylation and gene expression changes in well-defined colorectal cancer tissues with high purity. The integrated analysis gives additional insight regarding the regulation of colorectal cancer-associated genes and their underlying mechanisms that contribute to colorectal carcinogenesis.
    Matched MeSH terms: Epigenomics*
  8. Overview on Epigenetic Re-programming: A Potential Therapeutic Intervention in Triple Negative Breast Cancers
    Mohamad Hanif EA, Shah SA
    Asian Pac J Cancer Prev, 2018 Dec 25;19(12):3341-3351.
    PMID: 30583339
    Breast cancer treatments leads to variable responses. Hormonal therapy is beneficial to receptor positive breast cancer
    subtypes and display better clinical outcome than triple negative breast cancers (TNBCs) with FEC (5-Fluorouracil,
    Epirubicin and Cyclophosphamide) the mainstay chemotherapy regiment. Owning to their negative expressions of
    estrogen (ER), progesterone (PR) and HER2 receptors, disease recurrence and metastasis befalls some patients indicating
    resistance to FEC. Involvement of epigenetic silencing through DNA methylation, histone methylation, acetylation and
    sumoylation may be the key player in FEC chemoresistance. Epigenetic and molecular profiling successfully classified
    breast cancer subtypes, indicating potential driver mechanisms to the progression of TNBCs but functional mechanisms
    behind chemoresistance of these molecular markers are not well defined. Several epigenetic inhibitors and drugs have
    been used in the management of cancers but these attempts are mainly beneficial in hematopoietic cancers and not
    specifically favourable in solid tumours. Hypothetically, upon administration of epigenetic drugs, recovery of tumour
    suppressor genes is expected. However, high tendency of switching on global metastatic genes is predicted. Polycomb
    repressive complex (PRC) such as EZH2, SETD1A, DNMT, is known to have repressive effects in gene regulation and
    shown to inhibit cell proliferation and invasion in breast cancers. Individual epigenetic regulators may be an option
    to improve chemo-drug delivery in cancers. This review discussed on molecular signatures of various breast cancer
    subtypes and on-going attempts in understanding underlying molecular mechanisms of epigenetic regulators as well
    as providing insights on possible ways to utilize epigenetic enzymes/inhibitors with responses to chemotherapeutic
    drugs to re-program cellular and biological outcome in TNBCs.
    Matched MeSH terms: Epigenomics/methods
  9. Fulltext Cancer reversion with oocyte extracts is mediated by cell cycle arrest and induction of tumour dormancy
    Saad N, Alberio R, Johnson AD, Emes RD, Giles TC, Clarke P, et al.
    Oncotarget, 2018 Mar 23;9(22):16008-16027.
    PMID: 29662623 DOI: 10.18632/oncotarget.24664
    Inducing stable control of tumour growth by tumour reversion is an alternative approach to cancer treatment when eradication of the disease cannot be achieved. The process requires re-establishment of normal control mechanisms that are lost in cancer cells so that abnormal proliferation can be halted. Embryonic environments can reset cellular programmes and we previously showed that axolotl oocyte extracts can reprogram breast cancer cells and reverse their tumorigenicity. In this study, we analysed the gene expression profiles of oocyte extract-treated tumour xenografts to show that tumour reprogramming involves cell cycle arrest and acquisition of a quiescent state. Tumour dormancy is associated with increased P27 expression, restoration of RB function and downregulation of mitogen-activated signalling pathways. We also show that the quiescent state is associated with increased levels of H4K20me3 and decreased H4K20me1, an epigenetic profile leading to chromatin compaction. The epigenetic reprogramming induced by oocyte extracts is required for RB hypophosphorylation and induction of P27 expression, both occurring during exposure to the extracts and stably maintained in reprogrammed tumour xenografts. Therefore, this study demonstrates the value of oocyte molecules for inducing tumour reversion and for the development of new chemoquiescence-based therapies.
    Matched MeSH terms: Epigenomics
  10. Epigenetics in Metastatic Breast Cancer: Its Regulation and Implications in Diagnosis, Prognosis and Therapeutics
    Wu YS, Lee ZY, Chuah LH, Mai CW, Ngai SC
    Curr Cancer Drug Targets, 2019;19(2):82-100.
    PMID: 29714144 DOI: 10.2174/1568009618666180430130248
    Despite advances in the treatment regimen, the high incidence rate of breast cancer (BC) deaths is mostly caused by metastasis. Recently, the aberrant epigenetic modifications, which involve DNA methylation, histone modifications and microRNA (miRNA) regulations become attractive targets to treat metastatic breast cancer (MBC). In this review, the epigenetic alterations of DNA methylation, histone modifications and miRNA regulations in regulating MBC are discussed. The preclinical and clinical trials of epigenetic drugs such as the inhibitor of DNA methyltransferase (DNMTi) and the inhibitor of histone deacetylase (HDACi), as a single or combined regimen with other epigenetic drug or standard chemotherapy drug to treat MBCs are discussed. The combined regimen of epigenetic drugs or with standard chemotherapy drugs enhance the therapeutic effect against MBC. Evidences that epigenetic changes could have implications in diagnosis, prognosis and therapeutics for MBC are also presented. Several genes have been identified as potential epigenetic biomarkers for diagnosis and prognosis, as well as therapeutic targets for MBC. Endeavors in clinical trials of epigenetic drugs against MBC should be continued although limited success has been achieved. Future discovery of epigenetic drugs from natural resources would be an attractive natural treatment regimen for MBC. Further research is warranted in translating research into clinical practice with the ultimate goal of treating MBC by epigenetic therapy in the near future.
    Matched MeSH terms: Epigenomics
  11. Fulltext The Nigerian Bioinformatics and Genomics Network (NBGN): a collaborative platform to advance bioinformatics and genomics in Nigeria
    Fatumo S, Ebenezer TE, Ekenna C, Isewon I, Ahmad U, Adetunji C, et al.
    Glob Health Epidemiol Genom, 2020;5:e3.
    PMID: 32742665 DOI: 10.1017/gheg.2020.3
    Africa plays a central importance role in the human origins, and disease susceptibility, agriculture and biodiversity conservation. Nigeria as the most populous and most diverse country in Africa, owing to its 250 ethnic groups and over 500 different native languages is imperative to any global genomic initiative. The newly inaugurated Nigerian Bioinformatics and Genomics Network (NBGN) becomes necessary to facilitate research collaborative activities and foster opportunities for skills' development amongst Nigerian bioinformatics and genomics investigators. NBGN aims to advance and sustain the fields of genomics and bioinformatics in Nigeria by serving as a vehicle to foster collaboration, provision of new opportunities for interactions between various interdisciplinary subfields of genomics, computational biology and bioinformatics as this will provide opportunities for early career researchers. To provide the foundation for sustainable collaborations, the network organises conferences, workshops, trainings and create opportunities for collaborative research studies and internships, recognise excellence, openly share information and create opportunities for more Nigerians to develop the necessary skills to exceed in genomics and bioinformatics. NBGN currently has attracted more than 650 members around the world. Research collaborations between Nigeria, Africa and the West will grow and all stakeholders, including funding partners, African scientists, researchers across the globe, physicians and patients will be the eventual winners. The exponential membership growth and diversity of research interests of NBGN just within weeks of its establishment and the unanticipated attendance of its activities suggest the significant importance of the network to bioinformatics and genomics research in Nigeria.
    Matched MeSH terms: Epigenomics
  12. Fulltext Epigenetic Distribution of Recombinant Plant Chromosome Fragments in a Human-Arabidopsis Hybrid Cell Line
    Liaw Y, Liu Y, Teo C, Cápal P, Wada N, Fukui K, et al.
    Int J Mol Sci, 2021 May 21;22(11).
    PMID: 34063996 DOI: 10.3390/ijms22115426
    Methylation systems have been conserved during the divergence of plants and animals, although they are regulated by different pathways and enzymes. However, studies on the interactions of the epigenomes among evolutionarily distant organisms are lacking. To address this, we studied the epigenetic modification and gene expression of plant chromosome fragments (~30 Mb) in a human-Arabidopsis hybrid cell line. The whole-genome bisulfite sequencing results demonstrated that recombinant Arabidopsis DNA could retain its plant CG methylation levels even without functional plant methyltransferases, indicating that plant DNA methylation states can be maintained even in a different genomic background. The differential methylation analysis showed that the Arabidopsis DNA was undermethylated in the centromeric region and repetitive elements. Several Arabidopsis genes were still expressed, whereas the expression patterns were not related to the gene function. We concluded that the plant DNA did not maintain the original plant epigenomic landscapes and was under the control of the human genome. This study showed how two diverging genomes can coexist and provided insights into epigenetic modifications and their impact on the regulation of gene expressions between plant and animal genomes.
    Matched MeSH terms: Epigenomics/methods
  13. Epigenomic approach in understanding Alzheimer's disease and type 2 diabetes mellitus
    Shaik MM, Gan SH, Kamal MA
    CNS Neurol Disord Drug Targets, 2014 Mar;13(2):283-9.
    PMID: 24074446 DOI: 10.2174/18715273113126660181
    Cognitive decline is a debilitating feature of Alzheimer's disease (AD). The causes leading to such impairment are still poorly understood and effective treatments for AD are still unavailable. Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for AD due to desensitisation of insulin receptors in the brain. Recent studies have suggested that epigenetic mechanisms may also play a pivotal role in the pathogenesis of both AD and T2DM. This article describes the correlation between AD and T2DM and provides the insights to the epigenetics of AD. Currently, more research is needed to clarify the exact role of epigenetic regulation in the course and development of AD and also in relation to insulin. Research conducted especially in the earlier stages of the disease could provide more insight into its underlying pathophysiology to help in early diagnosis and the development of more effective treatment strategies.
    Matched MeSH terms: Epigenomics/methods*
  14. Fulltext Loss of Karma transposon methylation underlies the mantled somaclonal variant of oil palm
    Ong-Abdullah M, Ordway JM, Jiang N, Ooi SE, Kok SY, Sarpan N, et al.
    Nature, 2015 Sep 24;525(7570):533-7.
    PMID: 26352475 DOI: 10.1038/nature15365
    Somaclonal variation arises in plants and animals when differentiated somatic cells are induced into a pluripotent state, but the resulting clones differ from each other and from their parents. In agriculture, somaclonal variation has hindered the micropropagation of elite hybrids and genetically modified crops, but the mechanism responsible remains unknown. The oil palm fruit 'mantled' abnormality is a somaclonal variant arising from tissue culture that drastically reduces yield, and has largely halted efforts to clone elite hybrids for oil production. Widely regarded as an epigenetic phenomenon, 'mantling' has defied explanation, but here we identify the MANTLED locus using epigenome-wide association studies of the African oil palm Elaeis guineensis. DNA hypomethylation of a LINE retrotransposon related to rice Karma, in the intron of the homeotic gene DEFICIENS, is common to all mantled clones and is associated with alternative splicing and premature termination. Dense methylation near the Karma splice site (termed the Good Karma epiallele) predicts normal fruit set, whereas hypomethylation (the Bad Karma epiallele) predicts homeotic transformation, parthenocarpy and marked loss of yield. Loss of Karma methylation and of small RNA in tissue culture contributes to the origin of mantled, while restoration in spontaneous revertants accounts for non-Mendelian inheritance. The ability to predict and cull mantling at the plantlet stage will facilitate the introduction of higher performing clones and optimize environmentally sensitive land resources.
    Matched MeSH terms: Epigenomics*
  15. Fulltext Leucocytic DNA Methylation of Interleukin-6 Promoter Reduction in Pre-Hypertensive Young Adults
    Omar WFNW, Abdullah A, Talib NA, Shah ASM, Rahman JA
    Malays J Med Sci, 2019 Nov;26(6):46-54.
    PMID: 31908586 MyJurnal DOI: 10.21315/mjms2019.26.6.5
    Background: Pre-hypertension is associated with increased risk of cardiovascular disease. Chronic inflammation plays an important role in the pathophysiology of essential hypertension, with epigenetic dysregulation involvement. Nevertheless, the role of DNA methylation in prehypertensive state is unknown. The aim of this study was to investigate the association between DNA methylation level of interleukin-6 (IL-6) promoter in pre-hypertensive (PreHT) and normotensive (NT) young adults.

    Methods: A total of 80 NT and 80 PreHT healthy subjects aged between 18-45 years were recruited in Kuantan, Pahang, Malaysia using an observational cross-sectional study approach. DNA methylation level of IL-6 promoter in peripheral leukocytes were measured using bisulphite conversion and MethyLight assay.

    Results: There was no significant difference in age between NT and PreHT (P = 0.655). The mean blood pressure was 110(8)/73(5) mmHg in NT and 125(7)/82(5) mmHg in PreHT subjects. The IL-6 promoter methylation level was significantly lower in PreHT compared to NT subjects (P < 0.001).

    Conclusion: The current study demonstrates that hypomethylation of IL-6 promoter was associated with pre-hypertension in young adults. Thus, IL-6 methylation could be used as an early indicator for predicting hypertension and related risk of cardiovascular diseases in prehypertensive subjects. Gene expression and longitudinal studies are warranted to examine the methylation effect on IL-6 expression over time.

    Matched MeSH terms: Epigenomics
  16. Epigenetic modification: possible approach to reduce Salmonella enterica serovar enteritidis susceptibility under stress conditions
    Soleimani AF, Zulkifli I, Hair-Bejo M, Ebrahimi M, Jazayeri SD, Hashemi SR, et al.
    Avian Pathol, 2012;41(4):351-4.
    PMID: 22834548 DOI: 10.1080/03079457.2012.691155
    Stressors may influence chicken susceptibility to pathogens such as Salmonella enterica. Feed withdrawal stress can cause changes in normal intestinal epithelial structure and may lead to increased attachment and colonization of Salmonella. This study aimed to investigate modulatory effects of epigenetic modification by feed restriction on S. enterica serovar Enteritidis colonization in broiler chickens subjected to feed withdrawal stress. Chicks were divided into four groups: ad libitum feeding; ad libitum feeding with 24-h feed withdrawal on day 42; 60% feed restriction on days 4, 5, and 6; and 60% feed restriction on days 4, 5, and 6 with 24-h feed withdrawal on day 42. Attachment of S. Enteritidis to ileal tissue was determined using an ex vivo ileal loop assay, and heat shock protein 70 (Hsp70) expression was evaluated using sodium dodecyl sulphate-polyacrylamide gel electrophoresis and western blotting. Feed withdrawal stress increased S. Enteritidis attachment to ileal tissue. However, following feed withdrawal the epigenetically modified chickens had significantly lower attachment of S. Enteritidis than their control counterparts. A similar trend with a very positive correlation was observed for Hsp70 expression. It appears that epigenetic modification can enhance resistance to S. Enteritidis colonization later in life in chickens under stress conditions. The underlying mechanism could be associated with the lower Hsp70 expression in the epigenetically modified chickens.
    Matched MeSH terms: Epigenomics
  17. Exploring breast carcinogenesis through integrative genomics and epigenomics analyses
    Minning C, Mokhtar NM, Abdullah N, Muhammad R, Emran NA, Ali SA, et al.
    Int J Oncol, 2014 Nov;45(5):1959-68.
    PMID: 25175708 DOI: 10.3892/ijo.2014.2625
    There have been many DNA methylation studies on breast cancer which showed various methylation patterns involving tumour suppressor genes and oncogenes but only a few of those studies link the methylation data with gene expression. More data are required especially from the Asian region and to analyse how the epigenome data correlate with the transcriptome. DNA methylation profiling was carried out on 76 fresh frozen primary breast tumour tissues and 25 adjacent non-cancerous breast tissues using the Illumina Infinium(®) HumanMethylation27 BeadChip. Validation of methylation results was performed on 7 genes using either MS-MLPA or MS-qPCR. Gene expression profiling was done on 15 breast tumours and 5 adjacent non-cancerous breast tissues using the Affymetrix GeneChip(®) Human Gene 1.0 ST array. The overlapping genes between DNA methylation and gene expression datasets were further mapped to the KEGG database to identify the molecular pathways that linked these genes together. Supervised hierarchical cluster analysis revealed 1,389 hypermethylated CpG sites and 22 hypomethylated CpG sites in cancer compared to the normal samples. Gene expression microarray analysis using a fold-change of at least 1.5 and a false discovery rate (FDR) at p>0.05 identified 404 upregulated and 463 downregulated genes in cancer samples. Integration of both datasets identified 51 genes with hypermethylation with low expression (negative association) and 13 genes with hypermethylation with high expression (positive association). Most of the overlapping genes belong to the focal adhesion and extracellular matrix-receptor interaction that play important roles in breast carcinogenesis. The present study displayed the value of using multiple datasets in the same set of tissues and how the integrative analysis can create a list of well-focused genes as well as to show the correlation between epigenetic changes and gene expression. These gene signatures can help us understand the epigenetic regulation of gene expression and could be potential targets for therapeutic intervention in the future.
    Matched MeSH terms: Epigenomics
  18. Challenges and future direction of molecular research in air pollution-related lung cancers
    Shahadin MS, Ab Mutalib NS, Latif MT, Greene CM, Hassan T
    Lung Cancer, 2018 04;118:69-75.
    PMID: 29572006 DOI: 10.1016/j.lungcan.2018.01.016
    Hazardous air pollutants or chemical release into the environment by a variety of natural and/or anthropogenic activities may give adverse effects to human health. Air pollutants such as sulphur dioxide (SO2), nitrogen oxides (NOx), carbon monoxide (CO), heavy metals and particulate matter (PM) affect number of different human organs, especially the respiratory system. The International Agency for Research on Cancer (IARC) reported that ambient air pollution is a cause of lung cancer. Recently, the agency has classified outdoor air pollution as well as PM air pollution as Group 1 carcinogens. In addition, several epidemiological studies have shown a positive association between air pollutants to lung cancer risks and mortality. However, there are only a few studies examining the molecular effects of air pollution exposure specifically in lung cancer due to multiple challenges to mimic air pollution exposure in basic experimentation. Another major issue is the lack of adequate adjustments for exposure misclassification as air pollution may differ temporo-spatially and socioeconomically. Thus, the purpose of this paper is to review the current molecular understanding of air pollution-related lung cancer and potential future direction in this challenging yet important research field.
    Matched MeSH terms: Epigenomics
  19. Fulltext DNA methylation and exposure to ambient air pollution in two prospective cohorts
    Plusquin M, Guida F, Polidoro S, Vermeulen R, Raaschou-Nielsen O, Campanella G, et al.
    Environ Int, 2017 11;108:127-136.
    PMID: 28843141 DOI: 10.1016/j.envint.2017.08.006
    Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes. This study included blood-derived DNA methylation (Illumina-HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO2, NOx, PM2.5, PMcoarse, PM10, PM2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta-analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N=613) participants had both methylation and gene expression data available. Exposure to NO2 was associated with a significant global somatic hypomethylation (p-value=0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO2 and NOx. Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure-related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO2 and 9 for NOx mainly related to the immune system and its regulation. Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO2 and NOx. Functional differences in the immune system were suggested by transcriptome analyses.
    Matched MeSH terms: Epigenomics
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