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Transcript, methylation and molecular docking analyses of the effects of HDAC inhibitors, SAHA and Dacinostat, on SMN2 expression in fibroblasts of SMA patients

Mohseni J, Al-Najjar BO, Wahab HA, Zabidi-Hussin ZA, Sasongko TH

J Hum Genet, 2016 Sep;61(9):823-30.
PMID: 27251006 DOI: 10.1038/jhg.2016.61

Several histone deacetylase inhibitors (HDACis) are known to increase Survival Motor Neuron 2 (SMN2) expression for the therapy of spinal muscular atrophy (SMA). We aimed to compare the effects of suberoylanilide hydroxamic acid (SAHA) and Dacinostat, a novel HDACi, on SMN2 expression and to elucidate their acetylation effects on the methylation of the SMN2. Cell-based assays using type I and type II SMA fibroblasts examined changes in transcript expressions, methylation levels and protein expressions. In silico methods analyzed the intermolecular interactions between each compound and HDAC2/HDAC7. SMN2 mRNA transcript levels and SMN protein levels showed notable increases in both cell types, except for Dacinostat exposure on type II cells. However, combined compound exposures showed less pronounced increase in SMN2 transcript and SMN protein level. Acetylation effects of SAHA and Dacinostat promoted demethylation of the SMN2 promoter. The in silico analyses revealed identical binding sites for both compounds in HDACs, which could explain the limited effects of the combined exposure. With the exception on the effect of Dacinostat in Type II cells, we have shown that SAHA and Dacinostat increased SMN2 transcript and protein levels and promoted demethylation of the SMN2 gene.

Matched MeSH terms: DNA Methylation
Fulltext Tobacco smoking-associated genome-wide DNA methylation changes in the EPIC study

Ambatipudi S, Cuenin C, Hernandez-Vargas H, Ghantous A, Le Calvez-Kelm F, Kaaks R, et al.

Epigenomics, 2016 May;8(5):599-618.
PMID: 26864933 DOI: 10.2217/epi-2016-0001

AIM: Epigenetic changes may occur in response to environmental stressors, and an altered epigenome pattern may represent a stable signature of environmental exposure.
MATERIALS & METHODS: Here, we examined the potential of DNA methylation changes in 910 prediagnostic peripheral blood samples as a marker of exposure to tobacco smoke in a large multinational cohort.
RESULTS: We identified 748 CpG sites that were differentially methylated between smokers and nonsmokers, among which we identified novel regionally clustered CpGs associated with active smoking. Importantly, we found a marked reversibility of methylation changes after smoking cessation, although specific genes remained differentially methylated up to 22 years after cessation.
CONCLUSION: Our study has comprehensively cataloged the smoking-associated DNA methylation alterations and showed that these alterations are reversible after smoking cessation.

Matched MeSH terms: DNA Methylation*
The influence of folate and methionine on intestinal tumour development in the Apc(Min/+) mouse model

Teh AH, Symonds E, Bull C, Clifton P, Fenech M

Mutat Res Rev Mutat Res, 2012 05 22;751(1):64-75.
PMID: 22627043 DOI: 10.1016/j.mrrev.2012.05.001

Folate and methionine are critical for one-carbon metabolism impacting DNA synthesis, repair, and methylation processes, as well as polyamine synthesis. These micronutrients have been implicated in colorectal cancer risk. There are, however, inconsistencies within the literature, with some studies showing restriction to have tumour-inhibitory effects, whereas others suggest excess to have adverse outcomes. We conducted a review of the published data to examine the accumulated evidence for involvement of dietary folate and/or methionine restriction or excess in intestinal tumour development in the Apc(Min/+) mouse model, which is genetically prone to develop such cancers. Thirteen publications were selected for evaluation based on the following inclusion criteria: (i) use of Apc(Min/+) mouse model; (ii) interventions using dietary folate and/or methionine; and (iii) primary outcome measures focused on intestinal tumour development. We found that nutritional modulation of folate and methionine was shown to have different effects on intestinal cancer in the Apc(Min/+) mouse, depending on the dosage, duration and timing of intervention, and interaction of the Apc(Min/+) genotype with other genetic factors affecting folate and DNA methylation metabolism. Although some studies showed that folate deficiency before tumorigenesis tended to increase risk of tumour formation, there are inconsistencies regarding whether excess folate post-weaning or after tumour initiation increases intestinal tumour burden. Altogether, the pooled data do not appear to indicate a difference in effect on intestinal tumour incidence between post-weaning diets that are folate deficient or folate adequate. The Apc(Min/+) mouse is a useful model for assessment of the impact of dietary folate on intestinal tumour development, but further research is required to understand the reasons for these inconsistencies amongst studies based on likely mechanisms, including modulation of nucleotide synthesis, DNA methylation, and chromosomal instability, which may affect the rate of cellular division and its control.

Matched MeSH terms: DNA Methylation
Fulltext The epigenetics changes in childhood solid cancer: a review

Wan Faiziah Wan Abdul Rahman

Malaysian Journal of Paediatrics and Child Health, 2019;23(2):1-15.
MyJurnal

Epigenetics is the study of heritable changes in gene expression that do not involve changes to the underlying DNA sequence. It is a change in phenotype without changing in genotype which in turn affects how cellsread the genes. The epigenetic change is a regular occurrence but can also be influenced by several factors including age, environment, lifestyle, and disease state. It may have damaging effects that result in diseases like cancer. At least three systems including DNA methylation, histone modification and RNA-associated gene silencing are currently considered to initiate and sustain epigenetic change. New and ongoing research is continuously uncovering the role of epigenetics in a variety of diseases including in childhood solid cancer such as Ewing sarcoma, neuroblastoma, Wilms tumours, brain tumours and rhabdomyosarcoma. A better understanding of epigenetic changes in childhood cancers can guide towards future therapy and diagnosis.

Matched MeSH terms: DNA Methylation
Fulltext The complete methylome of Helicobacter pylori UM032

Lee WC, Anton BP, Wang S, Baybayan P, Singh S, Ashby M, et al.

BMC Genomics, 2015;16:424.
PMID: 26031894 DOI: 10.1186/s12864-015-1585-2

The genome of the human gastric pathogen Helicobacter pylori encodes a large number of DNA methyltransferases (MTases), some of which are shared among many strains, and others of which are unique to a given strain. The MTases have potential roles in the survival of the bacterium. In this study, we sequenced a Malaysian H. pylori clinical strain, designated UM032, by using a combination of PacBio Single Molecule, Real-Time (SMRT) and Illumina MiSeq next generation sequencing platforms, and used the SMRT data to characterize the set of methylated bases (the methylome).

Matched MeSH terms: DNA Methylation*
Fulltext The Unique Biology behind the Early Onset of Breast Cancer

Siddig A, Tengku Din TADA, Mohd Nafi SN, Yahya MM, Sulong S, Wan Abdul Rahman WF

Genes (Basel), 2021 03 05;12(3).
PMID: 33807872 DOI: 10.3390/genes12030372

Breast cancer commonly affects women of older age; however, in developing countries, up to 20% of breast cancer cases present in young women (younger than 40 years as defined by oncology literature). Breast cancer in young women is often defined to be aggressive in nature, usually of high histological grade at the time of diagnosis and negative for endocrine receptors with poor overall survival rate. Several researchers have attributed this aggressive nature to a hidden unique biology. However, findings in this aspect remain controversial. Thus, in this article, we aimed to review published work addressing somatic mutations, chromosome copy number variants, single nucleotide polymorphisms, differential gene expression, microRNAs and gene methylation profile of early-onset breast cancer, as well as its altered pathways resulting from those aberrations. Distinct biology behind early-onset of breast cancer was clear among estrogen receptor-positive and sporadic cases. However, further research is needed to determine and validate specific novel markers, which may help in customizing therapy for this group of patients.

Matched MeSH terms: DNA Methylation
Fulltext Sperm epigenetics landscape: correlation with embryo quality, reproductive outcomes and offspring's health

Garrido N, Boitrelle F, Saleh R, Durairajanayagam D, Colpi G, Agarwal A

Panminerva Med, 2023 Jun;65(2):166-178.
PMID: 37335245 DOI: 10.23736/S0031-0808.23.04871-1

Epigenetics refers to how gene expression and function are modulated without modifying the DNA sequence but through subtle molecular changes or interactions with it. As spermatogenesis progresses, male germ cells suffer plenty of epigenetic modifications, resulting in the definitive epigenome of spermatozoa conditioning its functionality, and this process can be altered by several internal and external factors. The paternal epigenome is crucial for sperm function, fertilization, embryo development, and offspring's health, and altered epigenetic states are associated with male infertility with or without altered semen parameters, embryo quality impairment, and worse ART outcomes together with the future offspring's health risks mainly through intergenerational transmission of epigenetic marks. Identifying epigenetic biomarkers may improve male factor diagnosis and the development of targeted therapies, not only to improve fertility but also to allow an early detection of risk and disease prevention in the progeny. While still there is much research to be done, hopefully in the near future, improvements in high-throughput technologies applied to epigenomes will permit our understanding of the underlying epigenetic mechanisms and the development of diagnostics and therapies leading to improved reproductive outcomes. In this review, we discuss the mechanisms of epigenetics in sperm and how epigenetics behave during spermatogenesis. Additionally, we elaborate on the relationship of sperm epigenetics with sperm parameters and male infertility, and highlight the impact of sperm epigenetic alterations on sperm parameters, embryo quality, ART outcomes, miscarriage rates and offspring's health. Furthermore, we provide insights into the future research of epigenetic alterations in male infertility.

Matched MeSH terms: DNA Methylation/genetics
Small RNAs and Karma methylation in Elaeis guineensis mother palms are linked to high clonal mantling

Ooi SE, Sarpan N, Taranenko E, Feshah I, Nuraziyan A, Roowi SH, et al.

Plant Mol Biol, 2023 Mar;111(4-5):345-363.
PMID: 36609897 DOI: 10.1007/s11103-022-01330-4

The mantled phenotype is an abnormal somaclonal variant arising from the oil palm cloning process and severe phenotypes lead to oil yield losses. Hypomethylation of the Karma retrotransposon within the B-type MADS-box EgDEF1 gene has been associated with this phenotype. While abnormal Karma-EgDEF1 hypomethylation was detected in mantled clones, we examined the methylation state of Karma in ortets that gave rise to high mantling rates in their clones. Small RNAs (sRNAs) were proposed to play a role in Karma hypomethylation as part of the RNA-directed DNA methylation process, hence differential expression analysis of sRNAs between the ortet groups was conducted. While no sRNA was differentially expressed at the Karma-EgDEF1 region, three sRNA clusters were differentially regulated in high-mantling ortets. The first two down-regulated clusters were possibly derived from long non-coding RNAs while the third up-regulated cluster was derived from the intron of a DnaJ chaperone gene. Several predicted mRNA targets for the first two sRNA clusters conversely displayed increased expression in high-mantling relative to low-mantling ortets. These predicted mRNA targets may be associated with defense or pathogenesis response. In addition, several differentially methylated regions (DMRs) were identified in Karma and its surrounding regions, mainly comprising subtle CHH hypomethylation in high-mantling ortets. Four of the 12 DMRs were located in a region corresponding to hypomethylated areas at the 3'end of Karma previously reported in mantled clones. Further investigations on these sRNAs and DMRs may indicate the predisposition of certain ortets towards mantled somaclonal variation.

Matched MeSH terms: DNA Methylation
Silencing of transgene expression in mammalian cells by DNA methylation and histone modifications in gene therapy perspective

Alhaji SY, Ngai SC, Abdullah S

Biotechnol Genet Eng Rev, 2019 Apr;35(1):1-25.
PMID: 30514178 DOI: 10.1080/02648725.2018.1551594

DNA methylation and histone modifications are vital in maintaining genomic stability and modulating cellular functions in mammalian cells. These two epigenetic modifications are the most common gene regulatory systems known to spatially control gene expression. Transgene silencing by these two mechanisms is a major challenge to achieving effective gene therapy for many genetic conditions. The implications of transgene silencing caused by epigenetic modifications have been extensively studied and reported in numerous gene delivery studies. This review highlights instances of transgene silencing by DNA methylation and histone modification with specific focus on the role of these two epigenetic effects on the repression of transgene expression in mammalian cells from integrative and non-integrative based gene delivery systems in the context of gene therapy. It also discusses the prospects of achieving an effective and sustained transgene expression for future gene therapy applications.

Matched MeSH terms: DNA Methylation
Silencing of suppressor of cytokine signaling-3 due to methylation results in phosphorylation of STAT3 in imatinib resistant BCR-ABL positive chronic myeloid leukemia cells

Al-Jamal HA, Jusoh SA, Yong AC, Asan JM, Hassan R, Johan MF

Asian Pac J Cancer Prev, 2014;15(11):4555-61.
PMID: 24969884

BACKGROUND: Silencing due to methylation of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator gene for the JAK/STAT signaling pathway has been reported to play important roles in leukemogenesis. Imatinib mesylate is a tyrosine kinase inhibitor that specifically targets the BCR-ABL protein and induces hematological remission in patients with chronic myeloid leukemia (CML). Unfortunately, the majority of CML patients treated with imatinib develop resistance under prolonged therapy. We here investigated the methylation profile of SOCS-3 gene and its downstream effects in a BCR-ABL positive CML cells resistant to imatinib.
MATERIALS AND METHODS: BCR-ABL positive CML cells resistant to imatinib (K562-R) were developed by overexposure of K562 cell lines to the drug. Cytotoxicity was determined by MTS assays and IC50 values calculated. Apoptosis assays were performed using annexin V-FITC binding assays and analyzed by flow cytometry. Methylation profiles were investigated using methylation specific PCR and sequencing analysis of SOCS-1 and SOCS-3 genes. Gene expression was assessed by quantitative real-time PCR, and protein expression and phosphorylation of STAT1, 2 and 3 were examined by Western blotting.
RESULTS: The IC50 for imatinib on K562 was 362 nM compared to 3,952 nM for K562-R (p=0.001). Percentage of apoptotic cells in K562 increased upto 50% by increasing the concentration of imatinib, in contrast to only 20% in K562-R (p<0.001). A change from non-methylation of the SOCS-3 gene in K562 to complete methylation in K562-R was observed. Gene expression revealed down- regulation of both SOCS-1 and SOCS-3 genes in resistant cells. STAT3 was phosphorylated in K562-R but not K562.
CONCLUSIONS: Development of cells resistant to imatinib is feasible by overexposure of the drug to the cells. Activation of STAT3 protein leads to uncontrolled cell proliferation in imatinib resistant BCR-ABL due to DNA methylation of the SOCS-3 gene. Thus SOCS-3 provides a suitable candidate for mechanisms underlying the development of imatinib resistant in CML patients.

Matched MeSH terms: DNA Methylation/genetics*
Screening of differential promoter hypermethylated genes in primary oral squamous cell carcinoma

Khor GH, Froemming GR, Zain RB, Abraham MT, Thong KL

Asian Pac J Cancer Prev, 2014;15(20):8957-61.
PMID: 25374236

BACKGROUND: Promoter hypermethylation leads to altered gene functions and may result in malignant cellular transformation. Thus, identification of biomarkers for hypermethylated genes could be useful for diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC).
OBJECTIVES: To screen hypermethylated genes with a microarray approach and to validate selected hypermethylated genes with the methylation-specific polymerase chain reaction (MSPCR).
MATERIALS AND METHODS: Genome-wide analysis of normal oral mucosa and OSCC tissues was conducted using the Illumina methylation microarray. The specified differential genes were selected and hypermethylation status was further verified with an independent cohort sample of OSCC samples. Candidate genes were screened using microarray assay and run by MSPCR analysis.
RESULTS: TP73, PIK3R5, and CELSR3 demonstrated high percentages of differential hypermethylation status.
CONCLUSIONS: Our microarray screening and MSPCR approaches revealed that the signature candidates of differentially hypermethylated genes may possibly become potential biomarkers which would be useful for diagnostic, prognostic and therapeutic targets of OSCC in the near future.

Matched MeSH terms: DNA Methylation*
Reelin (RELN) DNA methylation in the peripheral blood of schizophrenia

Nabil Fikri RM, Norlelawati AT, Nour El-Huda AR, Hanisah MN, Kartini A, Norsidah K, et al.

J Psychiatr Res, 2017 05;88:28-37.
PMID: 28086126 DOI: 10.1016/j.jpsychires.2016.12.020

The epigenetic changes of RELN that are involved in the development of dopaminergic neurons may fit the developmental theory of schizophrenia. However, evidence regarding the association of RELN DNA methylation with schizophrenia is far from sufficient, as studies have only been conducted on a few limited brain samples. As DNA methylation in the peripheral blood may mirror the changes taking place in the brain, the use of peripheral blood for a DNA methylation study in schizophrenia is feasible due to the scarcity of brain samples. Therefore, the aim of our study was to examine the relationship of DNA methylation levels of RELN promoters with schizophrenia using genomic DNA derived from the peripheral blood of patients with the disorder. The case control studies consisted of 110 schizophrenia participants and 122 healthy controls who had been recruited from the same district. After bisufhite conversion, the methylation levels of the DNA samples were calculated based on their differences of the Cq values assayed using the highly sensitive real-time MethyLight TaqMan® procedure. A significantly higher level of methylation of the RELN promoter was found in patients with schizophrenia compared to controls (p = 0.005) and also in males compared with females (p = 0.004). Subsequently, the RELN expression of the methylated group was 25 fold less than that of the non-methylated group. Based upon the assumption of parallel methylation changes in the brain and peripheral blood, we concluded that RELN DNA methylation might contribute to the pathogenesis of schizophrenia. However, the definite effects of methylation on RELN function during development and also in adult life still require further elaboration.

Matched MeSH terms: DNA Methylation/physiology*
Reactive oxygen species-induced alterations in H19-Igf2 methylation patterns, seminal plasma metabolites, and semen quality

Darbandi M, Darbandi S, Agarwal A, Baskaran S, Dutta S, Sengupta P, et al.

J Assist Reprod Genet, 2019 Feb;36(2):241-253.
PMID: 30382470 DOI: 10.1007/s10815-018-1350-y

PURPOSE: This study was conducted in order to investigate the effects of reactive oxygen species (ROS) levels on the seminal plasma (SP) metabolite milieu and sperm dysfunction.
METHODS: Semen specimens of 151 normozoospermic men were analyzed for ROS by chemiluminescence and classified according to seminal ROS levels [in relative light units (RLU)/s/106 sperm]: group 1 (n = 39): low (ROS DNA fragmentation index (DFI), chromatin maturation index (CMI), H19-Igf2 methylation status, and untargeted seminal metabolic profiling using nuclear magnetic resonance spectroscopy (1H-NMR), was carried out.
RESULT(S): The methylation status of H19 and Igf2 was significantly different in specimens with high ROS (P

Matched MeSH terms: DNA Methylation/genetics
Fulltext Prediction of clinical symptoms of Schizophrenia based on COMT Methylation marker

Nour El Huda Abd Rahim, Mohd Nabil Fikri Rahim, Norsidah Ku Zaifah, Hanisah Mohd Noor, Kartini Abdullah, Norlelawati A. Talib

International Medical Journal Malaysia, 2017;16(11):19-19.
MyJurnal

The dopamine hypothesis of schizophrenia is based on the fact that hyperdopaminergic
state is involved in causing psychosis and antipsychotic drugs block the
dopamine receptor. COMT regulates the homeostatic levels of neurotransmitter
dopamine in the synapses and plays a role in the neurocognitive function. The
dysregulation of dopamine in the prefrontal cortex influences the cognitive function and
the severity of the psychotic symptoms in schizophrenia. During epigenetic event,
methylated COMT gene may cause reduction in its expression and contribute to the
clinical presentation of schizophrenia. Therefore, the aim of this study was to assess the
feasibility of using COMT DNA methylation for the prediction of specific psychotic
presentation of schizophrenia. (Copied from article).

Matched MeSH terms: DNA Methylation
Fulltext Persistent DNA Methylation Changes across the First Year of Life and Prenatal NO2 Exposure in a Canadian Prospective Birth Study

Lee S, Sbihi H, MacIsaac JL, Balshaw R, Ambalavanan A, Subbarao P, et al.

Environ Health Perspect, 2024 Apr;132(4):47004.
PMID: 38573328 DOI: 10.1289/EHP13034

BACKGROUND: Evidence suggests that prenatal air pollution exposure alters DNA methylation (DNAm), which could go on to affect long-term health. It remains unclear whether DNAm alterations present at birth persist through early life. Identifying persistent DNAm changes would provide greater insight into the molecular mechanisms contributing to the association of prenatal air pollution exposure with atopic diseases.
OBJECTIVES: This study investigated DNAm differences associated with prenatal nitrogen dioxide (NO2) exposure (a surrogate measure of traffic-related air pollution) at birth and 1 y of age and examined their role in atopic disease. We focused on regions showing persistent DNAm differences from birth to 1 y of age and regions uniquely associated with postnatal NO2 exposure.
METHODS: Microarrays measured DNAm at birth and at 1 y of age for an atopy-enriched subset of Canadian Health Infant Longitudinal Development (CHILD) study participants. Individual and regional DNAm differences associated with prenatal NO2 (n=128) were identified, and their persistence at age 1 y were investigated using linear mixed effects models (n=124). Postnatal-specific DNAm differences (n=125) were isolated, and their association with NO2 in the first year of life was examined. Causal mediation investigated whether DNAm differences mediated associations between NO2 and age 1 y atopy or wheeze. Analyses were repeated using biological sex-stratified data.
RESULTS: At birth (n=128), 18 regions of DNAm were associated with NO2, with several annotated to HOX genes. Some of these regions were specifically identified in males (n=73), but not females (n=55). The effect of prenatal NO2 across CpGs within altered regions persisted at 1 y of age. No significant mediation effects were identified. Sex-stratified analyses identified postnatal-specific DNAm alterations.
DISCUSSION: Regional cord blood DNAm differences associated with prenatal NO2 persisted through at least the first year of life in CHILD participants. Some differences may represent sex-specific alterations, but replication in larger cohorts is needed. The early postnatal period remained a sensitive window to DNAm perturbations. https://doi.org/10.1289/EHP13034.

Matched MeSH terms: DNA Methylation*
Fulltext Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia

Wong KK, Lawrie CH, Green TM

Biomark Insights, 2019;14:1177271919846454.
PMID: 31105426 DOI: 10.1177/1177271919846454

Epigenetic alteration has been proposed to give rise to numerous classic hallmarks of cancer. Impaired DNA methylation plays a central role in the onset and progression of several types of malignancies, and DNA methylation is mediated by DNA methyltransferases (DNMTs) consisting of DNMT1, DNMT3A, and DNMT3B. DNMTs are frequently implicated in the pathogenesis and aggressiveness of acute myeloid leukaemia (AML) patients. In this review, we describe and discuss the oncogenic roles of DNMT1, DNMT3A, and DNMT3B in AML. The clinical response predictive roles of DNMTs in clinical trials utilising hypomethylating agents (azacitidine and decitabine) in AML patients are presented. Novel hypomethylating agent (guadecitabine) and experimental DNMT inhibitors in AML are also discussed. In summary, hypermethylation of tumour suppressors mediated by DNMT1 or DNMT3B contributes to the progression and severity of AML (except MLL-AF9 and inv(16)(p13;q22) AML for DNMT3B), while mutation affecting DNMT3A represents an early genetic lesion in the pathogenesis of AML. In clinical trials of AML patients, expression of DNMTs is downregulated by hypomethylating agents while the clinical response predictive roles of DNMT biomarkers remain unresolved. Finally, nucleoside hypomethylating agents have continued to show enhanced responses in clinical trials of AML patients, and novel non-nucleoside DNMT inhibitors have demonstrated cytotoxicity against AML cells in pre-clinical settings.

Matched MeSH terms: DNA Methylation
Fulltext Natural bioactive compounds targeting DNA methyltransferase enzymes in cancer: Mechanisms insights and efficiencies

Aanniz T, Bouyahya A, Balahbib A, El Kadri K, Khalid A, Makeen HA, et al.

Chem Biol Interact, 2024 Apr 01;392:110907.
PMID: 38395253 DOI: 10.1016/j.cbi.2024.110907

The regulation of gene expression is fundamental to health and life and is essentially carried out at the promoter region of the DNA of each gene. Depending on the molecular context, this region may be accessible or non-accessible (possibility of integration of RNA polymerase or not at this region). Among enzymes that control this process, DNA methyltransferase enzymes (DNMTs), are responsible for DNA demethylation at the CpG islands, particularly at the promoter regions, to regulate transcription. The aberrant activity of these enzymes, i.e. their abnormal expression or activity, can result in the repression or overactivation of gene expression. Consequently, this can generate cellular dysregulation leading to instability and tumor development. Several reports highlighted the involvement of DNMTs in human cancers. The inhibition or activation of DNMTs is a promising therapeutic approach in many human cancers. In the present work, we provide a comprehensive and critical summary of natural bioactive molecules as primary inhibitors of DNMTs in human cancers. The active compounds hold the potential to be developed as anti-cancer epidrugs targeting DNMTs.

Matched MeSH terms: DNA Methylation
Fulltext Methylenetetrahydrofolate Reductase CpG Islands: Epigenotyping

Wei LK, Sutherland H, Au A, Camilleri E, Haupt LM, Gan SH, et al.

J Clin Lab Anal, 2016 Jul;30(4):335-44.
PMID: 26109141 DOI: 10.1002/jcla.21860

BACKGROUND: Determination of the differential DNA methylation patterns of methylenetetrahydrofolate reductase (MTHFR) that are associated with differential MTHFR activity is important to understand the pathogenesis of ischemic stroke. However, to date, no data are available on the differential DNA methylation profiles of Kelantanese Malays. Therefore, we developed a rapid and efficient serial pyrosequencing assay to determine differential DNA methylation profiles of MTHFR, which help to further our understanding of the pathogenesis of ischemic stroke. The developed assay also served as the validation platform for our previous computational epigenetic research on MTHFR.
METHODS: Polymerase chain reaction primers were designed and validated to specifically amplify the cytosine that is followed by guanine residues (CpGs) A and B regions. Prior epigenotyping on 110 Kelantanese Malays, the serial pyrosequencing assays for the CpGs A and B regions were validated using five validation controls. The mean values of the DNA methylation profiles of CpGs A and B were calculated.
RESULTS: The mean DNA methylation levels for CpGs A and B were 0.984 ± 0.582 and 2.456 ± 1.406, respectively. The CpGs 8 and 20 showed the highest (5.581 ± 4.497) and the lowest (0.414 ± 2.814) levels of DNA methylation at a single-base resolution.
CONCLUSION: We have successfully developed and validated a pyrosequencing assay that is fast and can yield high-quality pyrograms for DNA methylation analysis and is therefore applicable to high throughput study. Using this newly developed pyrosequencing assay, the MTHFR DNA methylation profiles of 110 Kelantanese Malays were successfully determined. It also validated our computational epigenetic research on MTHFR.

Matched MeSH terms: DNA Methylation/genetics
Methylation of the filaggrin gene promoter does not affect gene expression and allergy

Tan HT, Ellis JA, Koplin JJ, Martino D, Dang TD, Suaini N, et al.

Pediatr Allergy Immunol, 2014 Oct;25(6):608-10.
PMID: 24912553 DOI: 10.1111/pai.12245
Matched MeSH terms: DNA Methylation*
Mechanisms of tumor cell resistance to the current targeted-therapy agents

Khamisipour G, Jadidi-Niaragh F, Jahromi AS, Zandi K, Hojjat-Farsangi M

Tumour Biol., 2016 Aug;37(8):10021-39.
PMID: 27155851 DOI: 10.1007/s13277-016-5059-1

Resistance to chemotherapy agents is a major challenge infront of cancer patient treatment and researchers. It is known that several factors, such as multidrug resistance proteins and ATP-binding cassette families, are cell membrane transporters that can efflux several substrates such as chemotherapy agents from the cell cytoplasm. To reduce the adverse effects of chemotherapy agents, various targeted-based cancer therapy (TBCT) agents have been developed. TBCT has revolutionized cancer treatment, and several agents have shown more specific effects on tumor cells than chemotherapies. Small molecule inhibitors and monoclonal antibodies are specific agents that mostly target tumor cells but have low side effects on normal cells. Although these agents have been very useful for cancer treatment, however, the presence of natural and acquired resistance has blunted the advantages of targeted therapies. Therefore, development of new options might be necessary. A better understanding of tumor cell resistance mechanisms to current treatment agents may provide an appropriate platform for developing and improving new treatment modalities. Therefore, in this review, different mechanisms of tumor cell resistance to chemotherapy drugs and current targeted therapies have been described.

Matched MeSH terms: DNA Methylation

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