1,720,995 research outputs found
Targeting the epigenome to treat neurodegenerative diseases or delay their onset: A perspective
Full text linkThe diagnostic potential of the epigenome in autism spectrum disorders
No full textThe diagnostic application of genome-wide methylation signatures is increasing in various syndromic forms of autism, but further studies are warranted to clarify whether epigenetic biomarkers can be of diagnostic utility in idiopathic ASD
One-carbon epigenetics and redox biology of neurodegeneration
No full textOne-carbon metabolism provides the methyl groups for both DNA and histone tail methylation reactions, two of the main epigenetic processes that tightly regulate the chromatin structure and gene expression levels. Several enzymes involved in one-carbon metabolism, as well as several epigenetic enzymes, are regulated by intracellular metabolites and redox cofactors, but their expression levels are in turn regulated by epigenetic modifications, in such a way that metabolism and gene expression reciprocally regulate each other to maintain homeostasis and regulate cell growth, survival, differentiation and response to environmental stimuli. Increasing evidence highlights the contribution of impaired one-carbon metabolism and epigenetic modifications in neurodegeneration. This article provides an overview of DNA and histone tail methylation changes in major neurodegenerative disorders, namely Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, discussing the contribution of oxidative stress and impaired one-carbon and redox metabolism to their onset and progression
Pregnancy loss and polymorphisms in folic acid genes
No full textFolates are essential vitamins required for DNA synthesis and cell division to support the development of the placenta and the fetus. Indeed, folate metabolism is the “core” part of one-carbon metabolism, a set of interconnected pathways that supply methyl groups for the synthesis of nucleic acids, amino acids, and S-adenosylmethionine (SAM), the main intracellular methylating agent. DNA methylation reactions are essential for mammalian development, playing a pivotal role in cell differentiation, maintenance of the cellular identity during mitosis, and parent-of-origin imprinting. Common polymorphisms of genes involved in folate metabolism can lead to impairments in DNA synthesis or methylation, thereby affecting cell growth and differentiation, and have been often investigated as potential risk factors for pregnancy loss. Among them, the MTHFR 677C>T polymorphism has been extensively investigated, and recent meta-analyses support a potential role as a maternal risk factor for recurrent pregnancy loss (RPL), particularly in Asians and developing countries. For all the other investigated polymorphisms in folate-related genes, including MTHFR 1298A>C, MTR 2756A>G, MTRR 66A>G, RFC1-43T>C, RFC1 80A>G, RFC1 696C>T, TCN2 67A>G, TCN2 776C>G, MTHFD1 1958G>A, and CBS 844ins68, data are still controversial, likely due to the scarce number of available case-control studies. In addition, several investigators suggest that haplotypes or combined genotypes of genes required for folate metabolism could account for RPL, but additional studies are required to clarify this issue
Epigenetics of neuromuscular disorders
No full textNeuromuscular disorders are a heterogeneous group of conditions affecting the neuromuscular system. The aim of this article is to review the major epigenetic findings in motor neuron diseases and major hereditary muscular dystrophies. DNA methylation changes are observed in both hereditary and sporadic forms, and combining DNA methylation analysis with mutational screening holds the potential for better diagnostic and prognostic accuracy. Novel, less toxic and more selective epigenetic drugs are designed and tested in animal and cell culture models of neuromuscular disorders, and non-coding RNAs are being investigated as either disease biomarkers or targets of therapeutic approaches to restore gene expression levels. Overall, neuromuscular disorder epigenetic biomarkers have a strong potential for clinical applications in the near future
Editorial: Shared Genetic Risk Factors Among Psychiatric Diseases and Other Medical Diseases and Traits
Full text linkEditorial in the Research Topic: Shared Genetic Risk Factors Among Psychiatric Diseases and Other Medical Diseases and Trait
Mitoepigenetics and Neurodegenerative Diseases
Full text linkMitochondrial impairment and increased oxidative stress are common features in neurodegenerative disorders, leading researchers to speculate that epigenetic changes in the mitochondrial DNA (mitoepigenetics) could contribute to neurodegeneration. The few studies performed so far to address this issue revealed impaired methylation levels of the mitochondrial regulatory region (D-loop region) in both animal models, postmortem brain regions, or circulating blood cells of patients with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Those studies also revealed that mtDNA D-loop methylation levels are subjected to a dynamic regulation within the progression of the neurodegenerative process, could be affected by certain neurodegenerative disease-causative mutations, and are inversely correlated with the mtDNA copy number. The methylation levels of other mtDNA regions than the D-loop have been scarcely investigated in human specimens from patients with neurodegenerative disorders or in animal models of the disease, and evidence of impaired methylation levels is often limited to a single study, making it difficult to clarify their correlation with mitochondrial dynamics and gene expression levels in these disorders. Overall, the preliminary results of the studies performed so far are encouraging making mitoepigenetics a timely and attractive field of investigation, but additional research is warranted to clarify the connections among epigenetic changes occurring in the mitochondrial genome, mitochondrial DNA dynamics and gene expression, and the neurodegenerative process
Polymorphisms of genes required for methionine synthesis and DNA methylation influence mitochondrial DNA methylation
No full textAim: Impaired methylation of the mitochondrial DNA and particularly in the regulatory displacement loop (D-loop) region, is increasingly observed in patients with neurodegenerative disorders. The present study aims to investigate if common polymorphisms of genes required for one-carbon metabolism (MTHFR, MTRR, MTR and RFC-1) and DNA methylation reactions (DNMT1, DNMT3A and DNMT3B) influence D-loop methylation levels. Materials & methods: D-loop methylation data were available from 133 late-onset Alzheimer's disease patients and 130 matched controls. Genotyping was performed with PCR-RFLP or high resolution melting techniques. Results: Both MTRR 66A > G and DNMT3A -448A > G polymorphisms were significantly associated with D-loop methylation levels. Conclusion: This exploratory study suggests that MTRR and DNMT3A polymorphisms influence mitochondrial DNA methylation; further research is required to better address this issue
Plasma homocysteine and polymorphisms of genes involved in folate metabolism correlate with DNMT1 gene methylation levels
Full text linkDNA methyltransferase 1 (DNMT1) is responsible for the maintenance of DNA methylation patterns during cell division. Several human diseases are characterized by impaired DNMT1 gene methylation, but less is known about the factors that regulate DNMT1 promoter methylation levels. Dietary folates and related B-vitamins are essential micronutrients for DNA methylation processes, and we performed the present study to investigate the contribution of circulating folate, vitamin B12, homocysteine, and common polymorphisms in folate pathway genes to the DNMT1 gene methylation levels. We investigated DNMT1 gene methylation levels in peripheral blood DNA samples from 215 healthy individuals. All the DNA samples were genotyped for MTHFR 677C > T (rs1801133) and 1298A > C (rs1801131), MTRR 66A > G (rs1801394), MTR 2756A > G (rs1805087), SLC19A1 (RFC1) 80G > A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp insertion/deletion (indel) (rs34489327), DNMT3A-448A > G (rs1550117), and DNMT3B-149C > T (rs2424913) polymorphisms. Circulating homocysteine, folate, and vitamin B12 levels were available from 158 of the recruited individuals. We observed an inverse correlation between plasma homocysteine and DNMT1 methylation levels. Furthermore, both MTR rs1805087 and TYMS rs34743033 polymorphisms showed a statistically significant effect on DNMT1 methylation levels. The present study revealed several correlations between the folate metabolic pathway and DNMT1 promoter methylation that could be of relevance for those disorders characterized by altered DNA methylation
Premature Aging Syndrome
No full textPremature aging syndromes are human conditions in which multiple organs and tissues show features of accelerated aging. This chapter describes Hutchinson–Gilford Progeria Syndrome and Werner Syndrome, two of the best-characterized segmental progeroid disorders in humans, and provides a summary of their main symptoms, genetic causes, molecular pathology, and therapeutic approaches. Furthermore, attention is paid to available cell culture models, including induced pluripotent stem cells and mouse models of both disorders, which represent invaluable tools for the investigation of their molecular mechanisms and for testing the effects of potential therapeutic compound
- …
