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Effect of Dnmt1 deficiency with and without folate deficiency on tumor numbers (A) and size distribution (B) in ApcMin mice in experiment 2. (A) Number of tumors ( SEM) is shown. The number of mice in each group is indicated beneath each vertical bar. (B) The size distribution (percentage, total value 1.0) of the tumors ( SEM) in each category is shown. *P 0.05, ANOVA, compared with the C/ group with the same diet.
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Although a number of studies have suggested that diets with low intake of folate, an important methyl donor, are associated with increased risks of colon cancer and its precursor the adenomatous polyp, the underlying mechanisms are poorly understood. Dysregulation and instability of DNA methylation and alterations in the levels of the predominant D...
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Context 1
... studies have reported that two single targeted mutations of Dnmt1, Dnmt S/ and Dnmt N/ , can decrease tumor numbers in Apc Min/ mice (27,28). Here, in both experiment 1 ( Figure 1A, control diet) and experiment 2 (Figure 2A, control diet), we show that a third single Dnmt1 mutation, in Dnmt C/ mice, is also associated with a decreased number of tumors in Apc Min/ mice. In addition, in both experiments, there was a significantly increased percentage of larger tumors in mice with wild-type Dnmt1 levels (Apc Min/ /Dnmt1 / ) as compared with mice with reduced levels of Dnmt1 (Apc Min/ / Dnmt C/ ) (Figures 1B and 2B). ...
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... the second experiment (Figure 2), the Apc Min/ /Dnmt C/ mice on the control diet had an average of only 20 2 tumors (Figure 2A), ~50% the number found for mice of the same genotype in the first experiment ( Figure 1A). Neither tumor Table I. ...
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... the second experiment (Figure 2), the Apc Min/ /Dnmt C/ mice on the control diet had an average of only 20 2 tumors (Figure 2A), ~50% the number found for mice of the same genotype in the first experiment ( Figure 1A). Neither tumor Table I. ...
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... values represent mean S.E.M. for 5-6 samples except for the DNA methylation (% methylated CCGG) results where n 3-6 samples. * Figure 2A) nor size distribution ( Figure 2B) were affected by 10 weeks of folate-deficient diet in the second experiment. ...
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... values represent mean S.E.M. for 5-6 samples except for the DNA methylation (% methylated CCGG) results where n 3-6 samples. * Figure 2A) nor size distribution ( Figure 2B) were affected by 10 weeks of folate-deficient diet in the second experiment. ...
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... was tested in the second experiment in which tumor numbers and size in Apc Min/ /Dnmt / mice on a control diet were compared with those Apc Min/ /Dnmt / mice on a folate- deficient diet. Mean tumor number in mice on the folate- deficient diet (54 6) was lower but not statistically different from those on the control diet (62 6, Figure 2A); in addition, the distribution of tumor sizes was nearly identical on the two different diets ( Figure 2B). Thus, in our model, 10 weeks of folate deficiency does not appear to accelerate tumorigenesis in Apc Min/ mice. ...
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... was tested in the second experiment in which tumor numbers and size in Apc Min/ /Dnmt / mice on a control diet were compared with those Apc Min/ /Dnmt / mice on a folate- deficient diet. Mean tumor number in mice on the folate- deficient diet (54 6) was lower but not statistically different from those on the control diet (62 6, Figure 2A); in addition, the distribution of tumor sizes was nearly identical on the two different diets ( Figure 2B). Thus, in our model, 10 weeks of folate deficiency does not appear to accelerate tumorigenesis in Apc Min/ mice. ...
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... assess the possibility of regional areas of hypomethylation in a normally methylated gene, we used bisulfite sequencing to evaluate the methylation status of 45 CpG sites in the exon 5-8 region of p53. Results for the Apc Min/ /Dnmt C/ and Apc Min/ /Dnmt / mice on the control diet, animals that exhibit large differences in tumor number (Figure 2A), are shown in Figure 4. For both genotypes, there was a similar level of methylation in the pre-neoplastic and tumor DNA, indicating that, in our model, Dnmt1 deficiency was not associated with hypomethylation of p53. ...
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Citations
... It's the DNA methyltransferases (DNMTs), specifically DNMT3a, DNMT3b, and DNMT1 that promote DNA methylation or hypermethylation (73). Where DNMT3a and 3b are important for de novo or "new" methylation, and DNMT1 is responsible for maintaining methylation during cell division (74,75). Alternatively, enzymes known as the 10-11 translocation (TET) enzymes (TET1, 2, and 3) remove methyl groups and are therefore responsible for demethylation or hypomethylation. ...
Skeletal muscle memory is an exciting phenomenon gaining significant traction across several scientific communities, amongst exercise practitioners and the public. Research has demonstrated that skeletal muscle tissue can be 'primed' by earlier positive encounters with exercise training that can enhance adaptation to later training, even following significant periods of exercise cessation or detraining. This review will describe and discuss the most recent research investigating the underlying mechanisms of skeletal muscle memory: 1) 'cellular' muscle memory and, 2) 'epigenetic' muscle memory as well as the emerging evidence of how these theories may work in synergy. We will discuss both 'positive' and 'negative' muscle memory and highlight the importance of investigating muscle memory for optimising exercise interventions and training programmes as well as the development of therapeutic strategies for counteracting muscle wasting conditions and age-related muscle loss. Finally, important directions emerging in the field will be highlighted to advance the next generation of studies in skeletal muscle memory research into the future.
... that a high percentage of hypomethylated regions due to maternal MD were localized on the X chromosome. Trasler and colleagues (2003) also did not observe changes in global methylation in the colon of mice predisposed to intestinal adenoma formation (Apc +/Min ) submitted to a low folate diet from weaning to 13 weeks of age with or without reductions in Dnmt1 expression due to heterozygous gene knockout (118) . ...
The intestinal tract is the entry gate for nutrients and symbiotic organisms, being in constant contact with external environment. DNA methylation is one of the keys to how environmental conditions, diet and nutritional status included, shape functionality in the gut and systemically. This review aims to summarize findings on the importance of methylation to gut development, differentiation, and function. Evidence to date on how external factors such diet, dietary supplements, nutritional status, and microbiota modifications modulate intestinal function through DNA methylation are also presented.
... The downstream molecules of SAM, S-adenosylhomocysteine (SAH) and HCY, are potentially cytotoxic substances and are known DNMT inhibitors that have a substantial effect on inducing hypomethylation. [45][46][47][48] Under normal conditions, SAM will donate a methyl group to the substrate before transforming to SAH, which undergoes hydrolysis to give HCY, 49 and SAM can then be regenerated from HCY via the formation of methionine by transmethylation, a metabolic cycle that requires a constant supply of folate and vitamin B12. In a folate and vitamin B 12 -deficient environment, the imbalanced one-carbon metabolism leads to the disturbed transformation of HCY and reduced SAM production, which, in turn, affects downstream DNA methylation and increases amyloidogenesis possibly through the upregulation of Bace1 and Psen1 transcripts. ...
Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide and causes severe financial and social burdens. Despite much research on the pathogenesis of AD, the neuropathological mechanisms remain obscure and current treatments have proven ineffective. In the past decades, transgenic rodent models have been used to try to unravel this disease, which is crucial for early diagnosis and the assessment of disease-modifying compounds. In this review, we focus on transgenic rodent models used to study amyloid-beta pathology in AD. We also discuss their possible use as promising tools for AD research. There is still no effective treatment for AD and the development of potent therapeutics are urgently needed. Many molecular pathways are susceptible to AD, ranging from neuroinflammation, immune response, and neuroplasticity to neurotrophic factors. Studying these pathways may shed light on AD pathophysiology as well as provide potential targets for the development of more effective treatments. This review discusses the advantages and limitations of these models and their potential therapeutic implications for AD.
... The downstream molecules of SAM, S-adenosylhomocysteine (SAH) and HCY, are potentially cytotoxic substances and are known DNMT inhibitors that have a substantial effect on inducing hypomethylation. [45][46][47][48] Under normal conditions, SAM will donate a methyl group to the substrate before transforming to SAH, which undergoes hydrolysis to give HCY, 49 and SAM can then be regenerated from HCY via the formation of methionine by transmethylation, a metabolic cycle that requires a constant supply of folate and vitamin B12. In a folate and vitamin B 12 -deficient environment, the imbalanced one-carbon metabolism leads to the disturbed transformation of HCY and reduced SAM production, which, in turn, affects downstream DNA methylation and increases amyloidogenesis possibly through the upregulation of Bace1 and Psen1 transcripts. ...
Alzheimer's disease (AD) is a debilitating disorder that manifests with amyloid beta plaque deposition, neurofibrillary tangles, neuronal loss, and severe cognitive impairment. Although much effort has been made to decipher the pathogenesis of this disease, the mechanisms causing these detrimental outcomes remain obscure. Over the past few decades, neuroepigenetics has emerged as an important field that, among other things, explores how reversible modifications can change gene expression to control behavior and cognitive abilities. Among epigenetic modifications, DNA methylation requires further elucidation for the conflicting observations from AD research and its pivotal role in learning and memory. In this review, we focus on the essential components of DNA methylation, the effects of aberrant methylation on gene expressions in the amyloidogenic pathway and neurochemical processes, as well as memory epigenetics in Alzheimer's disease.
... DNA methylation is also regulated by DNA methyltransferases (DNMTs) (Fig. 10.1). DNMT1 helps maintain methylation once the modification has occurred, whereas DNMT 3a and b control de novo methylation of a gene (Trasler et al., 2003). Alternatively, DNA methylation removal (demethylation) is performed via two methods; (1) active demethylation, occurs via the ten-eleven translocation (TET) enzymes, including TET1, 2 and 3 that convert the 5mC to 5-hydroxymethyl cytosine (5hmC) which then removes the methyl group through a base excision repair mechanism (Tahiliani et al., 2009;Ito et al., 2010) (Fig. 10.1). ...
Molecular exercise physiology is the study of the underlying molecular regulatory mechanisms that underpin physiological adaptation to exercise. The molecular mechanisms studied include; inherited DNA traits and mutations (genetics), extracellular and intracellular signaling, gene expression, and protein translation in the major tissues and organs that are required for exercise, particularly skeletal muscle. Within the molecular exercise physiology field, epigenetics is an emerging and exciting area that is beginning to enhance our understanding of how environmental exposures to exercise can affect the regulation of our inherited DNA, affecting the extent to which genes are turned on and off (gene/mRNA expression). DNA methylation is one of the major epigenetic modifications that can regulate gene expression following environmental encounters with exercise without changes to the genetic code. Therefore, this chapter provides an overview of our current understanding for the role of DNA methylation in response to acute aerobic and resistance exercise, as well as its function in regulating gene expression following chronic exercise. Finally, we review the emerging and exciting area of epigenetic muscle memory and the role of DNA methylation in this phenomenon, and provide important directions for future research in this area.
... In fact, chemical exposure may affect only specific genomic regions and/or induce a combination of hypomethylated and hypermethylated regions that average each other in a global DNA methylation assay. Furthermore, it was shown that DNMT1-deficient mice are capable of maintaining normal levels of DNA methylation (Trasler et al., 2003) and that downregulation of dnmt transcription could be associated with DNA hypermethylation in human (Bönsch et al., 2006), overall supporting the complexity behind epigenetic regulation. ...
A number of chemicals have been shown to affect epigenetic patterning and functions. Since epigenetic mechanisms regulate transcriptional networks, epigenetic changes induced by chemical exposure can represent early molecular events for long-term adverse physiological effects. Epigenetics has thus appeared as a research field of major interest within (eco)toxicological sciences. The present study aimed at measuring effects on epigenetic-related mechanisms of selected environmental chemicals (bisphenols, perfluorinated chemicals, methoxychlor, permethrin, vinclozolin and coumarin 47) in zebrafish embryos and liver cells (ZFL). Transcription of genes related to DNA methylation and histone modifications was measured and global DNA methylation was assessed in ZFL cells using the LUMA assay. The differences in results gathered from both models suggest that chemicals affect different mechanisms related to epigenetics in embryos and cells. In zebrafish embryos, exposure to bisphenol A, coumarin 47, methoxychlor and permethrin lead to significant transcriptional changes in epigenetic factors suggesting that they can impact early epigenome reprogramming related to embryonic development. In ZFL cells, significant transcriptional changes were observed upon exposure to all chemicals but coumarin 47; however, only perfluorooctane sulfonate induced significant effects on global DNA methylation. Notably, in contrast to the other tested chemicals, perfluorooctane sulfonate affected only the expression of the histone demethylase kdm5ba. In addition, kdm5ba appeared as a sensitive gene in zebrafish embryos as well. Taken together, the present results suggest a role for kdm5ba in regulating epigenetic patterns in response to chemical exposure, even though mechanisms remain unclear. To confirm these findings, further evidence is required regarding changes in site-specific histone marks and DNA methylation together with their long-term effects on physiological outcomes.
... The process of DNA methylation is orchestrated via a group of enzymes called DNA methyltransferases. De-novo methyltransferases 3a and 3b (DNMT3a/3b, respectively) are able to methylate nonmethylated cytosine residues via the donation of a methyl group from s-adenosyl methionine (SAM), producing 5mC and s-adenosyl homocysteine (SAH; Figure 1.7) (Trasler et al., 2003). To remove the cytosine modification ( Figure 1.7), the ten-eleven translocation methylcytosine dioxygenase 1 (TET 1) enzyme and other members of the TET protein family, catalyse the conversion of 5mC to 5-hydroxy-methylcytoseine (5hmC) via oxidation of 5mC in an iron and alpha-ketoglutarate dependent reaction (Ito et al., 2010). ...
Skeletal muscle mass is vitally important for the maintenance of health and quality of life into old age, with a plethora of disorders and diseases linked to the loss of this tissue. As a consequence, molecular biologists have extensively investigated both atrophying and hypertrophying skeletal muscle, in order to understand the molecular pathways that are induced to evoke both loss and growth of skeletal muscle. Despite huge progressions in the field, a full understanding of the molecular mechanisms that orchestrate growth and loss in skeletal muscle, remain elusive. In this regard, epigenetics, referring to alterations in gene expression via structural modifications of DNA without fundamental alterations of the DNA code, have recently become a promising area of research, specifically for its role in modulating genetic expression. However, the field of skeletal muscle epigenetics is in its infancy, and as such, there is currently a distinct paucity of research investigating this biological phenomenon. Herein, a genomic approach was utilised to examine the role DNA methylation plays in modulating the response, at both a genetic and phenotypic level, of mammalian skeletal muscle. The methodological and analytical approaches utilised in this thesis identify a number of important, novel and impactful findings. Firstly, it is identified that DNA methylation displays a distinct inverse relationship with gene expression during both muscular atrophy and hypertrophy, these findings are furthered by work identifying that DNA methylation alterations may precede functional changes in gene expression during skeletal muscle hypertrophy. This thesis also elucidated that skeletal muscle possesses an epigenetic memory that creates an enhanced adaptive response to resistance load induced hypertrophy, when the same stimulus was previously encountered. Finally, in human subjects, a number of novel and previously unstudied gene transcripts were identified that display significantly positive correlations with changes in skeletal muscle mass, as evoked by resistance training.
The data in this thesis demonstrates an important role for DNA methylation in regulating skeletal muscle mass during periods of both muscle atrophy and hypertrophy, respectively. The work presented here may allow for further work to be conducted, expanding our understanding of epigenetics in skeletal muscle and best facilitating the development of therapeutics that may alleviate the detrimental effects observed during periods of skeletal muscle atrophy.
... DNMT1 was closely related to abnormal methylation of DNA in intestinal tumors [94]. Reduced Dnmt1 expression in Apc Min/+ DNMT1 C/+ mice significantly decreased the number of intestinal tumors compared to Apc Min/+ mice [95]. Furthermore, the Apc Min/+ HLTF −/− mouse model showed that loss of helicase-like transcription factor (HLTF) expression significantly induces the formation of small intestinal adenomas and colon cancer [96]. ...
The ApcMin/+ mouse, carrying an inactivated allele of the adenomatous polyposis coli (Apc) gene, is a widely used animal model of human colorectal tumorigenesis. While crossed with other gene knockout or knock-in mice, these mice possess advantages in investigation of human intestinal tumorigenesis. Intestinal tumor pathogenesis involves multiple gene alterations; thus, various double gene deficiency models could provide novel insights into molecular mechanisms of tumor biology, as well as gene-gene interactions involved in intestinal tumor development and assessment of novel strategies for preventing and treating intestinal cancer. This review discusses approximately 100 double gene deficient mice and their associated intestinal tumor development and progression phenotypes. The dual gene knockouts based on the Apc mutation background consist of inflammation and immune-related, cell cycle-related, Wnt/β-catenin signaling-related, tumor growth factor (TGF)-signaling-related, drug metabolism-related, and transcription factor genes, as well as some oncogenes and tumor suppressors. Future studies should focus on conditional or inducible dual or multiple mouse gene knockout models to investigate the molecular mechanisms underlying intestinal tumor development, as well as potential drug targets.
... The study explains that Aß oligomers lower DNMT activity and increase the expression of APP and PS1, but folic acid supplementation increased the activity of DNMT and lowered the expression of APP and PS1 that resulted in the partial cell viability [66]. It is also established that SAH acts as a potential inhibitor of DNMT by product inhibition, and it also results in achieving hypomethylation of the genome [67,68]. In AD, it has been seen that methionine S-adenosyl transferase, CSF folate, and brain CSF are significantly decreased [69][70][71]; however, SAH level in brain increases [72]. ...
Research over the years has shown that causes of Alzheimer’s disease are not well understood, but over the past years, the involvement of epigenetic mechanisms in the developing memory formation either under pathological or physiological conditions has become clear. The term epigenetics represents the heredity of changes in phenotype that are independent of altered DNA sequences. Different studies validated that cytosine methylation of genomic DNA decreases with age in different tissues of mammals, and therefore, the role of epigenetic factors in developing neurological disorders in aging has been under focus. In this review, we summarized and reviewed the involvement of different epigenetic mechanisms especially the DNA methylation in Alzheimer’s disease (AD), late-onset Alzheimer’s disease (LOAD), familial Alzheimer’s disease (FAD), and autosomal dominant Alzheimer’s disease (ADAD). Down to the minutest of details, we tried to discuss the methylation patterns like mitochondrial DNA methylation and ribosomal DNA (rDNA) methylation. Additionally, we mentioned some therapeutic approaches related to epigenetics, which could provide a potential cure for AD. Moreover, we reviewed some recent studies that validate DNA methylation as a potential biomarker and its role in AD. We hope that this review will provide new insights into the understanding of AD pathogenesis from the epigenetic perspective especially from the perspective of DNA methylation.
... This initiates the generation of tetraploid cells, misoriented spindles and misaligned chromosomes and leads to cell cycle defects, alterations in cell proliferation and apoptosis. As well, a reduced crypt to villus migration was observed in these mice (274). ...
