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Results for “methylation dysregulation”

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At least 19 recordsLinked to original sources

PubMed2026

ReMeDy: A Flexible Statistical Framework for Region-Based Detection of DNA Methylation Dysregulation.

Region-based epigenome-wide association studies have demonstrated improved statistical power and biological interpretability compared with probe-wise analyses of DNA methylation data. However, most existing region-based methods characterize methylation dysregulation primarily through changes in mean methylation levels associated with a phenotype of interest. Substantial evidence indicates that phenotype-associated methylation alterations may also manifest through changes in methylation variability or through joint shifts in mean and variability. Despite this, no existing statistical framework jointly models mean-variance methylation changes in a region-based manner. We propose ReMeDy, a flexible statistical framework that uses a hierarchical likelihood approach within a generalized linear model setting to identify differentially methylated regions, variably methylated regions, and regions exhibiting joint differential and variable methylation at a genome-wide scale. Unlike existing models, ReMeDy operates directly on biologically defined co-methylated regions, allowing it to naturally capture spatial correlation inherent in DNA methylation array data, while avoiding reliance on heuristic, user-defined tuning parameters such as smoothing spans and kernel bandwidths that can substantially influence results and introduce subjectivity. Through extensive simulation studies and comprehensive benchmarking against popular models, we demonstrate that ReMeDy maintains false discovery and Type-I error rates at nominal levels while achieving consistently higher statistical power across a wide range of realistic scenarios. Application to population-level DNA methylation data further shows that ReMeDy identifies biologically meaningful regions and pathways implicated in complex human diseases that are not captured by conventional mean-based analyses alone. ReMeDy is implemented as an open-source R package and is freely available at https://github.com/SChatLab/ReMeDy.

DNA Methylation↗

PubMedDate not supplied

Evidence that DNA methylation imbalance is not involved in the development of malignant mesothelioma.

Methylation dysregulation has been a consistent finding in various malignancies, particularly those where the pathogenetic mechanisms are unclear. In order to test the hypothesis that methylation imbalance may not be a feature of cancers where the aetiologic agent or process is known, we studied the methylation status of the myogenic genes Myf-3 and Myf-4 by Southern blotting in malignant mesothelioma, a cancer strongly associated with asbestos exposure. DNA samples obtained from controls and mesothelioma patients did not exhibit hypermethylation of Myf-3 and hypomethylation of Myf-4, as noted in malignant lymphomas. The methylation status of Myf-3 and Myf-4 in malignant mesothelioma was similar to that of non-malignant cells indicating that dysregulation of the DNA methylating machinery may not be involved in mesothelioma development. The present findings do not support the view that methylation imbalance is a consequence of neoplastic transformation, but indicate that it may be one of the early molecular events involved in the genesis of some cancers.

Asbestos↗

PubMed2006

A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus.

The expression of imprinted genes is mediated by allele-specific epigenetic modification of genomic DNA and chromatin, including parent of origin-specific DNA methylation. Dysregulation of these genes causes a range of disorders affecting pre- and post-natal growth and neurological function. We investigated a cohort of 12 patients with transient neonatal diabetes whose disease was caused by loss of maternal methylation at the TNDM locus. We found that six of these patients showed a spectrum of methylation loss, mosaic with respect to the extent of the methylation loss, the tissues affected and the genetic loci involved. Five maternally methylated loci were affected, while one maternally methylated and two paternally methylated loci were spared. These patients had higher birth weight and were more phenotypically diverse than other TNDM patients with different aetiologies, presumably reflecting the influence of dysregulation of multiple imprinted genes. We propose the existence of a maternal hypomethylation syndrome, and therefore suggest that any patient with methylation loss at one maternally-methylated locus may also manifest methylation loss at other loci, potentially complicating or even confounding the clinical presentation.

Birth Weight↗

PubMed1995

Differential sensitivity to loss of cytosine methyl groups within the hepatic p53 gene of folate/methyl deficient rats.

Dietary folate/methyl deficiency provides a unique model of endogenous hepatocarcinogenesis in which to study progressive alterations in DNA methylation patterns during tumor progression in vivo. Weanling male F344 rats were given a semi-purified diet deficient in the methyl donors choline, methionine and folic acid for a period of 9 weeks. Using a genomic sequencing procedure based on the PCR amplification of bisulfite-modified DNA, the methylation status of individual CpG sites within exons 6 and 7 of the p53 gene in liver samples from control and deficient rats was determined. Treatment of denatured nuclear DNA with sodium bisulfite quantitatively converts all cytosine residues to uracil which are then amplified as thymine in the PCR reaction. In contrast, 5-methylcytosine is resistant to bisulfite deamination under the reaction conditions and is amplified as cytosine. Automated sequencing of bisulfite-modified DNA will then elucidate the methylation status of each cytosine residue within a defined gene sequence. In addition to evaluation of the methylation status of the p53 gene, the relative activity of the DNA methyltransferase was also quantified in nuclear extracts from control and folate/methyl deficient rats. The results indicate that specific 5-methyl cytosines within the hepatic p53 gene from methyl deficient rats are resistant to demethylation despite the diet-induced decrease in S-adenosylmethionine and the increase in cell proliferation associated with this dietary intervention. Progressive demethylation was observed at other methylated cytosine residues in folate/methyl deficient rats after 9 weeks despite a paradoxical increase in DNA methyltransferase activity. The application of this sequence-specific technology will allow the definition of the methylation status of every CpG site within a coding sequence or promoter region and should provide new insights into mechanisms and consequences of methylation dysregulation during progressive multistage carcinogenesis.

Animals↗

PubMed2004

Evidence that general genomic hypomethylation and focal hypermethylation are two independent molecular events of non-Hodgkin's lymphoma.

Changes in the DNA methylation profile, including general genomic hypomethylation and regional hypermethylation, have been shown to coexist in many neoplastic tissues. However, the relationship between, and significance of, these different forms of DNA methylation dysregulation in disease onset, progression, or maintenance remains unclear. Previously, our work has shown that the CpG dinucleotide-rich gene Myf-3 is hypermethylated in most cases of malignant lymphoproliferative disease (LPD). However, it is unknown whether malignant transformation of lymphoid cells is associated with general genomic hypomethylation and whether regional hypermethylation is restricted to CpG islands. The relationship between the status of general genomic methylation and the methylation of CpG and non-CpG islands can be clearly investigated in DNA from tumors of patients suffering malignant LPD, as monoclonalilty of malignant cells in LPD can be readily confirmed. In this study, the relationships between the methylation status of a region of the PAX7 paired box, which is not contained within a CpG island, general genomic hypomethylation, and the methylation status of Myf-3 was examined in 24 cases of LPD. Results revealed that hypermethylation of the PAX7 paired box is strongly associated with hypermethylation of Mvf-3, indicating the abnormal hypermethylating activity in malignant lymphoid cells does not specifically target CpG islands. Further, general genomic hypomethylation was shown to be associated with malignant LPD but not with regional hypermethylation, indicating that the mechanisms responsible for the generation of each of these disturbed DNA methylation phenotypes act independently as one of a number of permissive but not essential steps in the malignant transformation of lymphoid cells.

Case-Control Studies↗

PubMed2000

Cancer genetics/epigenetics and the X chromosome: possible new links for malignant glioma pathogenesis and immune-based therapies.

Human high-grade gliomas (HGGs) are rapidly progressing heterogeneous brain tumors of unknown etiology and there are no effective treatment modalities available. The recent discovery of cancer-specific antigens has opened new doors for specific tumor-targeted treatments using passive and active immunotherapeutic strategies. In particular, SEREX (serological analysis of recombinant cDNA expression libraries) has aided in the discovery of numerous new tumor antigens. These specific tumor antigens are located on chromosome X and are expressed predominantly in the testes among normal organs, and hence termed Cancer/Testis Antigens (CTAs). We found that the vast majority of HGG patients overexpress a receptor for an immune regulatory cytokine, interleukin 13 (IL-13), which differs from the normal tissue physiological receptor. Interestingly, the HGG-associated receptor protein, IL-13R alpha, is expressed solely in the testes and its gene is localized to chromosome X, which mirror the expression pattern and genomic localization of CTAs. There is little evidence for frequent gross structural abnormalities on chromosome X in HGG. Although the mechanism that causes X chromosome-linked CTAs to be aberrantly expressed in tumors is not fully understood, evidence is beginning to point toward the DNA methylation dysregulation that occurs in tumor cells as being implicit in this process and perhaps in the oncogenic process as well. Therefore, further study of the phenomenon of CTAs may bring the dual benefit of better understanding tumorigenesis and providing new molecular tools for better management of HGGs. Also, we propose that the X chromosome may in fact be an important player in HGG oncogenesis.

Antigens, Neoplasm↗

PubMed2026

Integrative methylation and miRNA dysregulation in dlPFC reveal distinct molecular signatures of suicide and non-suicide subtypes in major depressive disorder.

AIM: Major depressive disorder (MDD) is a leading cause of disability and carries a high risk of suicide. MicroRNAs (miRNAs) are epigenetic regulators implicated in MDD and can be regulated by DNA methylation, potentially reshaping downstream gene networks. We investigated methylation-linked miRNA dysregulation and explored whether these changes are specifically associated with suicide among MDD patients. METHODS: Genome-wide DNA methylation profiling of the dorsolateral prefrontal cortex from 15 MDD patients who died by suicide (MDD+S), 17 MDD patients who died from causes other than suicide (MDD-S), and 16 controls (C) using the Illumina 850K MethylationEPIC array was integrated with small RNA sequencing-based miRNA quantification to identify miRNA-associated differentially methylated probes (DMPs), link methylation to miRNA expression, and infer downstream targets and pathways. RESULTS: Differential methylation analysis (P ≤ 0.05) revealed 139 miRNA-linked DMPs in C vs. MDD+/-S, 135 in C vs. MDD-S, 179 in C vs. MDD+S, and the highest in MDD+S vs. MDD-S (235). CpG-miRNA pairing (within 1500kb promoter) followed by Spearman correlation identified inverse associations between CpG β values and miRNA expression, with the most consistent signals in suicide-status-stratified subsets, including cg06341821-hsa-miR-574-3p and cg25451306-hsa-miR-2110 in MDD+S-related contrasts, and cg06179179-hsa-miR-595 in MDD-S-related contrasts. High-confidence target prediction and ClueGO enrichment indicated distinct biology: miR-595 target genes in MDD-S were enriched for interferon/innate immune signaling, whereas miR-2110 target genes in MDD+S were enriched for ligand-gated ion channel activity and synaptic/receptor signaling. CONCLUSION: This integrated approach identifies methylation-regulated miRNA pathways that may play key roles in the molecular pathogenesis of MDD and suicide.

Humans↗

PubMed2004

Reversal of phencyclidine-induced dopaminergic dysregulation by N-methyl-D-aspartate receptor/glycine-site agonists.

N-methyl-D-aspartate (NMDA) receptors may play a critical role in the pathophysiology of schizophrenia. In rodents, NMDA receptor antagonists, such as phencyclidine (PCP), induce dopaminergic dysregulation that resembles the pattern observed in schizophrenia. The present study investigates the degree to which concurrent treatment with NMDA modulators, such as glycine and the recently developed glycine transport antagonist N[3-(4"-fluorophenyl)-3-(4"-phenylphenoxy)propyl]sarcosine (NFPS) prevents dopaminergic dysregulation observed following chronic (3 months) or subchronic (2 weeks) PCP administration. Both chronic and subchronic treatment with PCP in the absence of glycine or NFPS led to significant potentiation of amphetamine-induced dopamine release in the prefrontal cortex and striatum, similar to that observed in schizophrenia. Treatment with either high-dose glycine or NFPS along with PCP prevented PCP effects. These findings demonstrate effective doses of glycine for use in animal models of schizophrenia, and support recent clinical studies showing the effectiveness of NMDA agonists in the treatment of persistent symptoms of schizophrenia.

Amphetamine↗

PubMed1998

Inhibition of poly(ADP-ribose) polymerase: reduction of ischemic injury and attenuation of N-methyl-D-aspartate-induced neurotransmitter dysregulation.

BACKGROUND AND PURPOSE: The nuclear enzyme poly(ADP-ribose) polymerase (PARP) may play a role in DNA repair. However, in cerebral ischemia, excessive PARP activation may lead to energy depletion and exacerbation of neuronal damage. We examined the effect of inhibiting PARP on (1) the degree of cerebral injury in a rat model of transient focal ischemia and (2) the degree of neurotransmitter dysregulation induced by local cortical perfusion of N-methyl-D-aspartate (NMDA). METHODS: In experiment 1, rats were subjected to transient ischemia for 90 minutes by occlusion of the middle cerebral artery. After 22.5 hours of reperfusion, lesions were quantified by tetrazolium staining. Untreated rats were compared with those treated with the PARP inhibitor 3-aminobenzamide (10 mg/kg). In experiment 2, rats were implanted with microdialysis probes in the cortex, and 1 mmol/L NMDA was perfused for 2 hours. Extracellular concentrations of neurotransmitter and neuromodulator amino acids were measured. Untreated rats were compared with those given 10 mg/kg 3-aminobenzamide. RESULTS: In experiment 1, PARP inhibition significantly reduced lesion volumes: 204+/-43 mm3 (untreated) versus 90+/-24 mm3 (treated). Neuroprotection was primarily manifested in the cortex. In experiment 2, NMDA perfusion resulted in large elevations of glutamate, taurine, and the lipid component phosphoethanolamine. Levels of the NMDA site modulator D-serine were reduced, and glycine levels appeared unchanged. 3-Aminobenzamide significantly attenuated the elevations in glutamate and phosphoethanolamine but had no effects on D-serine and glycine. CONCLUSIONS: Inhibition of PARP reduced injury after transient focal ischemia in rats and attenuated NMDA-induced glutamate efflux and overall neurotransmitter dysregulation. The deleterious effects of excessive PARP activation may be related in part to amplification of excitotoxicity, possibly by cellular energy depletion and additional transmitter release and/or reduced reuptake.

Animals↗

PubMed2026

Epigenetic and immunological alterations in umbilical cord blood of overweight/obese women with gestational diabetes mellitus: insights into DNA methylation signatures and immune cell dysregulation.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse maternal and neonatal outcomes. Epigenetic modifications may reflect intrauterine metabolic exposure and contribute to immune and metabolic alterations. This study aimed to explore DNA methylation profiles in umbilical cord blood from overweight and obese women with and without GDM. METHODS: Umbilical cord blood samples from 30 overweight/obese pregnant women (with and without GDM) were analyzed using the Illumina 850 K methylation array to identify differentially methylated positions (DMPs) and regions (DMRs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to assess the functional relevance of methylation changes. Immune cell composition was estimated using deconvolution analysis and further examined in an independent single-cell RNA sequencing (scRNA-seq) cohort. Lasso regression was applied to identify CpG sites associated with GDM status and construct a preliminary methylation-based classification model. RESULTS: A total of 23,331 hypermethylated and 29,501 hypomethylated DMPs were identified between women with and without GDM, with hypomethylation predominating. Enrichment analyses indicated associations with neurodevelopmental pathways, metabolic processes, immune regulation, and epigenetic modification. Immune deconvolution analysis suggested reduced proportions of CD4+ T cells (p < 0.05) and a trend toward decreased NK cells in the GDM group, alongside increased CD8+ T cells and neutrophils. Seven CpG sites were selected for model construction and demonstrated strong discriminatory performance within this cohort. CONCLUSION: This exploratory study identifies distinct cord blood DNA methylation patterns associated with GDM in overweight/obese pregnancies. The findings suggest potential links between epigenetic alterations and immune cell composition in GDM-exposed offspring. The identified CpG signature warrants further validation in larger, prospective cohorts to determine its clinical applicability.

Humans↗

PubMed2026

Ensemble DNA methylation clock demonstrates Immune-metabolic aging signatures associated with mortality.

Aging is a multifactorial process that is best described in terms of the progressive acquisition of multiple layers of phenotypic changes, such as epigenetic modifications, inflammation, and metabolic dysregulation. DNA methylation clocks have been extensively used to construct epigenetic clocks based on the DNAm profiles that can be used to estimate biological age and predict age-associated outcomes. Nevertheless, the vast majority of clocks constructed so far have been based on linear models, which are unlikely to fully account for the heterogeneity and non-linearity of survival-related DNAm signatures. In this work, we constructed a heterogeneous stacked ensemble survival model based on DNAm data obtained from the Framingham Heart Study. We first identified 190 CpG loci using elastic net Cox regression and subsequently constructed a survival prediction model based on the fusion of five complementary survival models by means of a neural network meta-learner. The prediction power of the survival model was evaluated in an external validation cohort, where we observed strong performance for predicting all-cause mortality that significantly exceeded PhenoAge and was statistically comparable to GrimAge. These performance estimates were derived in cohorts of European ancestry and externally validated in postmenopausal women aged 50-79 years, and should therefore be interpreted as applicable only to demographically similar populations.

Humans↗

PubMed2005

Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model.

Folate is an essential co-factor in the remethylation of homocysteine to methionine, thereby ensuring the supply of S-adenosylmethionine, the methyl group donor for most biological methylations, including that of DNA. Aberrant patterns and dysregulation of DNA methylation are consistent events in carcinogenesis and hence, DNA methylation is considered to be mechanistically related to the development of cancer. Folate deficiency appears to increase the risk of several malignancies, and aberrant DNA methylation has been considered to be a leading mechanism by which folate deficiency enhances carcinogenesis. Although diets deficient in methyl group donors (choline, folate, methionine and vitamin B12) have been consistently observed to induce DNA hypomethylation, the effect of an isolated folate deficiency on DNA methylation remains highly controversial and unresolved. Whether or not isolated folate deficiency can modulate DNA methylation is an important issue because it would establish a mechanistic link between folate deficiency and cancer. We examined the effects of isolated folate deficiency on methionine cycle intermediates, genomic and site-specific DNA methylation and DNA methyltransferase in an in vitro model of folate deficiency, using untransformed NIH/3T3 and CHO-K1 cells, and human HCT116 and Caco-2 colon cancer cells. Our data demonstrate that the effect of folate deficiency on the methionine cycle pathway and DNA methylation in these cells is highly complex and appears to depend on the cell type and stage of transformation, and may be gene and site-specific. The direction of changes of methionine cycle intermediates in response to folate deficiency is not uniformly consistent with the known biochemical effect of folate on the methionine cycle pathway. Moreover, the effect of folate deficiency on DNA methylation appears to be mediated by both methionine cycle intermediate-dependent and independent pathways.

Animals↗

PubMed2001

Loss of expression of HDAC-recruiting methyl-CpG-binding domain proteins in human cancer.

Dysregulation of CpG-methylation is a common feature of many human cancers and tumour suppressor genes can be silenced by hypermethylation. Recently, 2 methyl-CpG-binding domain proteins have been linked to gene inactivation by their ability to recruit co-repressors and HDAC-activity to methylated gene promoters. Here, we have analysed mRNA expression of these genes, MeCP2 and MBD2, in a wide variety of primary human tumours. In solid tumours, expression levels of MBD2 (57/71) and MeCP2 (64/71) were significantly reduced in the majority of primary tumours as detected by quantitative real-time RT-PCR. Western blot analyses of MeCP2 in matched tumour-normal samples of patients with non-small-cell lung cancer (NSCLC) indicated reduced protein in a significant percentage of patients. In acute myelogenous leukaemia (n = 26), expression levels were only slightly reduced and did not differ between samples analysed at diagnosis or at the time of relapse. In early-stage NSCLC (n = 70) expression of MeCP2 and MBD2 was significantly lower in squamous cell carcinoma than in adenocarcinoma or large cell carcinoma (P = 0.03 and P = 0.01). To further elucidate the mechanisms of gene regulation, we analysed MeCP2 and MBD2 regulation during haematopoietic differentiation. No significant changes in MeCP2 or MBD2 expression were found when NB4 cells were differentiated toward granulocytes suggesting that neither differentiation nor cell cycle status were relevant for the reduced expression of these genes in human cancer. In conclusion, the significant loss of MeCP2 and MBD2 expression in human cancers suggests a potential role of this phenomenon in the development of solid human tumours.

Cell Differentiation↗

PubMed2003

Genomic hypomethylation in neoplastic cells from dogs with malignant lymphoproliferative disorders.

DNA methylation is an epigenetic modification in which a methyl group is added usually to the fifth carbon position of a cytosine residue. Dysregulation of this process is an important molecular event which has been shown to be associated with neoplastic transformation and tumour progression in humans and mice. Features of methylation dysregulation in many different types of neoplasms include general genomic hypomethylation, focal hypermethylation, and altered expression of genes which encode a series of DNA (cytosine-5) methyltransferases. Interestingly, many types of neoplasia that are recognised in humans also develop spontaneously in the dog. By comparing the restriction patterns of MspI and HpaII, this study demonstrates that as in human, genomic hypomethylation is a feature of neoplastic cells in the majority of canine lymphoma cases and approximately one-third of canine leukemia cases confirming that dysregulation of the DNA methylating machinery is implicated in malignant transformation of lymphoid cells in some dogs.

Animals↗

PubMed2006

Radiation-induced genomic instability is associated with DNA methylation changes in cultured human keratinocytes.

The mechanism by which radiation-induced genomic instability is initiated, propagated and effected is currently under intense scrutiny. We have investigated the potential role of altered genomic methylation patterns in the cellular response to irradiation and have found evidence for widespread dysregulation of CpG methylation persisting up to 20 population doublings post-irradiation. Similar effects are seen with cells treated with medium from irradiated cells (the 'bystander effect') rather than subjected to direct irradiation. Using an arbitrarily primed methylation sensitive PCR screening method we have demonstrated that irradiation causes reproducible alterations in the methylation profile of a human keratinocyte cell line, HPV-G, and have further characterised one of these sequences as being a member of a retrotransposon element derived sequence family on chromosome 7; MLT1A. Multiple changes were also detected in the screen, which indicate that although the response of cells is predominantly hypermethylation, specific hypomethylation occurs as well. Sequence specific changes are also reported in the methylation of the pericentromeric SAT2 satellite sequence. This is the first demonstration that irradiation results in the induction of heritable methylation changes in mammalian cells, and provides a link between the various non-radiological instigators of genomic instability, the perpetuation of the unstable state and several of its manifestations.

Base Sequence↗

PubMed2005

Upstream CpG island methylation of the PAX3 gene in human rhabdomyosarcomas.

BACKGROUND: Adult tumors can be characterized by hypermethylation of CpG islands associated with 5'-upstream and coding regions of specific genes. This hypermethylation can also be part of the aging process. In contrast, much less is known about gene hypermethylation in childhood cancers, where methylation changes are not part of the aging process but likely represent developmental dysregulation. PAX3 is an important gene in muscle development and muscle-producing neoplasms such as rhabdomyosarcomas. PROCEDURES: We examined the methylation status of a PAX3 5'-CpG island in rhabdomyosarcoma subtypes and in normal fetal skeletal muscle. PAX3 methylation was analyzed in 15 embryonal rhabdomyosarcomas, 12 alveolar rhabdomyosarcomas, and in six normal skeletal muscle samples, using semi-quantitative PCR analysis of DNA digested with methyl-sensitive restriction enzymes. RESULTS: The CpG island in the upstream region of the human PAX3 gene was hypermethylated in the majority of ERMS examined (13 of 15 tumors, mean of 52% methylation), whereas most ARMS (9 of 12 tumors) and all normal muscle samples showed relative hypomethylation (both 18% mean methylation). Various CpG sites differ in contribution to overall PAX3 CpG island methylation, with methylation at a HaeII site being inversely correlated with PAX3 expression. CONCLUSIONS: PAX3 CpG island methylation appears to distinguish embryonal subtype of rhabdomyosarcoma from alveolar, and methylation at certain sites within this CpG island is inversely correlated with PAX3 expression. In addition to exemplifying developmental dysregulation, methylation of PAX3 has potential in the development of an epigenetic profile for the diagnosis of rhabdomyosarcoma.

Child↗

PubMed2004

Dysregulation of gene expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse substantia nigra.

Parkinson's disease pathogenesis proceeds through several phases, culminating in the loss of dopaminergic neurons of the substantia nigra (SN). Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of oxidative SN injury is frequently used to study degeneration of dopaminergic neurons in mice and non-human primates, an understanding of the temporal sequence of molecular events from inhibition of mitochondrial complex 1 to neuronal cell death is limited. Here, microarray analysis and integrative data mining were used to uncover pathways implicated in the progression of changes in dopaminergic neurons after MPTP administration. This approach enabled the identification of small, yet consistently significant, changes in gene expression within the SN of MPTP-treated animals. Such an analysis disclosed dysregulation of genes in three main areas related to neuronal function: cytoskeletal stability and maintenance, synaptic integrity, and cell cycle and apoptosis. The discovery and validation of these alterations provide molecular evidence for an evolving cascade of injury, dysfunction, and cell death.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2005

Nutritional epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility.

The inheritance of information based on gene expression levels is known as epigenetics, as opposed to genetics, which refers to information transmitted on the basis of gene sequence. In contrast to genetic changes observed in cancer, epigenetic changes are gradual in onset and are progressive, their effects are dose-dependent and are potentially reversible. These observations present new opportunities in cancer-risk modification and prevention using dietary and lifestyle factors and potential chemopreventive drugs. In this regard, folate, a water-soluble B vitamin, has been a focus of intense interest because of an inverse association between folate status and the risk of several malignancies (in particular, colorectal cancer) and of its potential ability to modulate DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. Aberrant patterns and dysregulation of DNA methylation are mechanistically related to colorectal carcinogenesis. Folate plays an essential role in one-carbon transfer involving re-methylation of homocysteine to methionine, thereby ensuring the provision of S-adenosylmethionine, the primary methyl group donor for most biological methylation reactions. The portfolio of evidence from animal, human, and in vitro studies suggests that the effects of folate deficiency and supplementation on DNA methylation are gene and site specific, and appear to depend on cell type, target organ, stage of transformation, and the degree and duration of folate depletion.

Animals↗