scholarly journals DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons from Alzheimer’s, Related Tauopathies and Genetic Tauopathies

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3064
Author(s):  
Geraldine Zimmer-Bensch ◽  
Hans Zempel
Keyword(s):  
Dna Methylation ◽  
Current Knowledge ◽  
Ectopic Expression ◽  
Premature Death ◽  
Epigenetic Mechanism ◽  
Neurological Deficits ◽  
Diagnostic Tools ◽  
Epigenetic Therapy ◽  
Disease Etiology ◽  
Mapt Gene

Genetic and sporadic forms of tauopathies, the most prevalent of which is Alzheimer’s Disease, are a scourge of the aging society, and in the case of genetic forms, can also affect children and young adults. All tauopathies share ectopic expression, mislocalization, or aggregation of the microtubule associated protein TAU, encoded by the MAPT gene. As TAU is a neuronal protein widely expressed in the CNS, the overwhelming majority of tauopathies are neurological disorders. They are characterized by cognitive dysfunction often leading to dementia, and are frequently accompanied by movement abnormalities such as parkinsonism. Tauopathies can lead to severe neurological deficits and premature death. For some tauopathies there is a clear genetic cause and/or an epigenetic contribution. However, for several others the disease etiology is unclear, with few tauopathies being environmentally triggered. Here, we review current knowledge of tauopathies listing known genetic and important sporadic forms of these disease. Further, we discuss how DNA methylation as a major epigenetic mechanism emerges to be involved in the disease pathophysiology of Alzheimer’s, and related genetic and non-genetic tauopathies. Finally, we debate the application of epigenetic signatures in peripheral blood samples as diagnostic tools and usages of epigenetic therapy strategies for these diseases.

scholarly journals DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons From Alzheimers, Related Tauopathies and Genetic Tauopathies

2021 ◽  
Author(s):  
Geraldine Zimmer-Bensch ◽  
Hans Zempel
Keyword(s):  
Dna Methylation ◽  
Current Knowledge ◽  
Ectopic Expression ◽  
Premature Death ◽  
Epigenetic Mechanism ◽  
Neurological Deficits ◽  
Epigenetic Therapy ◽  
Disease Etiology ◽  
Mapt Gene ◽  
Epigenetic Signatures

Genetic and sporadic forms of tauopathies, the most prevalent of which is Alzheimer’s Disease, are a scourge of the aging society, and in case of genetic forms, can also affect children and young adults. All tauopathies share ectopic expression, mislocalization, or aggregation of the microtubule associated protein TAU, encoded by the MAPT gene. As TAU is a neuronal protein widely expressed in the CNS, the overwhelming majority of tauopathies are neurological disorders. They are characterized by cognitive dysfunction often leading to dementia, and are frequently accompanied by movement abnormalities such as parkinsonism. Tauopathies can lead to severe neurological deficits and premature death. For some tauopathies there is a clear genetic cause and/ or an epigenetic contribution. However, for several others the disease etiology is unclear, with few tauopathies being environmentally triggered. Here we review current knowledge of tauopathies listing known genetic and important sporadic forms of this disease. Further, we discuss how DNA methylation as a major epigenetic mechanism emerges to be involved in the disease pathophysiology of Alzheimer’s, and related genetic and non-genetic tauopathies. Finally, we debate the application of epigenetic signatures in peripheral blood samples as diagnostic tool and usage of epigenetic therapy strategies for these diseases.

scholarly journals DNA methylation in thyroid cancer

2019 ◽  
Vol 26 (7) ◽  
pp. R415-R439 ◽  
Author(s):  
Carles Zafon ◽  
Joan Gil ◽  
Beatriz Pérez-González ◽  
Mireia Jordà
Keyword(s):  
Dna Methylation ◽  
Thyroid Cancer ◽  
Cancer Genomics ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Epigenetic Mechanism ◽  
Aberrant Methylation ◽  
Technological Advances ◽  
Molecular Landscape

In recent years, cancer genomics has provided new insights into genetic alterations and signaling pathways involved in thyroid cancer. However, the picture of the molecular landscape is not yet complete. DNA methylation, the most widely studied epigenetic mechanism, is altered in thyroid cancer. Recent technological advances have allowed the identification of novel differentially methylated regions, methylation signatures and potential biomarkers. However, despite recent progress in cataloging methylation alterations in thyroid cancer, many questions remain unanswered. The aim of this review is to comprehensively examine the current knowledge on DNA methylation in thyroid cancer and discuss its potential clinical applications. After providing a general overview of DNA methylation and its dysregulation in cancer, we carefully describe the aberrant methylation changes in thyroid cancer and relate them to methylation patterns, global hypomethylation and gene-specific alterations. We hope this review helps to accelerate the use of the diagnostic, prognostic and therapeutic potential of DNA methylation for the benefit of thyroid cancer patients.

scholarly journals Epigenetic Basis of Molecular Changes in Animal Cells with Particular Regard to Embryonic Development – A Review / Epigenetyczne Podstawy Przemian Molekularnych Zachodzących W Komórkach Zwierzęcych, Ze Szczególnym Uwzględnieniem Rozwoju Embrionalnego – Artykuł Przeglądowy

2013 ◽  
Vol 13 (4) ◽  
pp. 675-685
Author(s):  
Joanna Romanek
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Embryonic Development ◽  
De Novo ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
Epigenetic Mechanism ◽  
Animal Cells ◽  
Molecular Changes ◽  
De Novo Methylation

Abstract Regulation of gene expression is a complex process. Epigenetics is the study of heritable changes in gene expression independently of DNA sequence. Epigenetic control of gene transcription is based on two main processes. The first is reversible DNA methylation, primarily of cytosine at position C5, rarely in position N3, or of adenine at position C6 (Xu et al., 2010). The second process is the change in chromatin structure and function by chemical modification of histones, including mainly methylation, acetylation, and phosphorylation of histone amino acids (Zamudio et al., 2008). During development and differentiation of cells, changes occur in DNA methylation of genes. After fertilization there are dynamic histone modifications and changes in DNA methylation in zygotes. Use of methylation sensitive restriction enzymes causes a global demethylation in the early embryonic stage (Sulewska et al., 2007 b). De novo methylation of CpG sites is followed by embryo implantation. Next, during gastrulation most genes are methylated except the tissue-specific genes. The last wave of de novo methylation takes place during the gametogenesis and is dependent on sex (Sulewska et al., 2007 b). The aim of this work is to review the current knowledge about epigenetic mechanism of molecular changes in animal cells with particular regard to embryonic development.

scholarly journals Circulating miRNAs Related to Epithelial–Mesenchymal Transitions (EMT) as the New Molecular Markers in Endometriosis

2021 ◽  
Vol 43 (2) ◽  
pp. 900-916
Author(s):  
Anna Zubrzycka ◽  
Monika Migdalska-Sęk ◽  
Sławomir Jędrzejczyk ◽  
Ewa Brzeziańska-Lasota
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Symptoms ◽  
Diagnostic Tools ◽  
Endometrial Stromal Cells ◽  
Disease Etiology ◽  
Diagnostic Biomarkers ◽  
Mesenchymal Transition ◽  
Non Invasive

Endometriosis is a chronic gynecological disease defined by the presence of endometrial-like tissue found outside the uterus, most commonly in the peritoneal cavity. Endometriosis lesions are heterogenous but usually contain endometrial stromal cells and epithelial glands, immune cell infiltrates and are vascularized and innervated by nerves. The complex etiopathogenesis and heterogenity of the clinical symptoms, as well as the lack of a specific non-invasive diagnostic biomarkers, underline the need for more advanced diagnostic tools. Unfortunately, the contribution of environmental, hormonal and immunological factors in the disease etiology is insufficient, and the contribution of genetic/epigenetic factors is still fragmentary. Therefore, there is a need for more focused study on the molecular mechanisms of endometriosis and non-invasive diagnostic monitoring systems. MicroRNAs (miRNAs) demonstrate high stability and tissue specificity and play a significant role in modulating a range of molecular pathways, and hence may be suitable diagnostic biomarkers for the origin and development of endometriosis. Of these, the most frequently studied are those related to endometriosis, including those involved in epithelial–mesenchymal transition (EMT), whose expression is altered in plasma or endometriotic lesion biopsies; however, the results are ambiguous. Specific miRNAs expressed in endometriosis may serve as diagnostics markers with prognostic value, and they have been proposed as molecular targets for treatment. The aim of this review is to present selected miRNAs associated with EMT known to have experimentally confirmed significance, and discuss their utility as biomarkers in endometriosis.

scholarly journals Salivary DNA Methylation as an Epigenetic Biomarker for Head and Neck Cancer. Part I: A Diagnostic Accuracy Meta-Analysis

2021 ◽  
Vol 11 (6) ◽  
pp. 568
Author(s):  
Óscar Rapado-González ◽  
Cristina Martínez-Reglero ◽  
Ángel Salgado-Barreira ◽  
Laura Muinelo-Romay ◽  
Juan Muinelo-Lorenzo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Head And Neck Cancer ◽  
Diagnostic Accuracy ◽  
Head And Neck ◽  
Likelihood Ratio ◽  
Neck Cancer ◽  
Meta Analysis ◽  
Positive Likelihood Ratio ◽  
Epigenetic Mechanism ◽  
Cochrane Library

DNA hypermethylation is an important epigenetic mechanism for gene expression inactivation in head and neck cancer (HNC). Saliva has emerged as a novel liquid biopsy representing a potential source of biomarkers. We performed a comprehensive meta-analysis to evaluate the overall diagnostic accuracy of salivary DNA methylation for detecting HNC. PubMed EMBASE, Web of Science, LILACS, and the Cochrane Library were searched. Study quality was assessed by the Quality Assessment for Studies of Diagnostic Accuracy-2, and sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (dOR), and their corresponding 95% confidence intervals (CIs) were calculated using a bivariate random-effect meta-analysis model. Meta-regression and subgroup analyses were performed to assess heterogeneity. Eighty-four study units from 18 articles with 8368 subjects were included. The pooled sensitivity and specificity of salivary DNA methylation were 0.39 and 0.87, respectively, while PLR and NLR were 3.68 and 0.63, respectively. The overall area under the curve (AUC) was 0.81 and the dOR was 8.34. The combination of methylated genes showed higher diagnostic accuracy (AUC, 0.92 and dOR, 36.97) than individual gene analysis (AUC, 0.77 and dOR, 6.02). These findings provide evidence regarding the potential clinical application of salivary DNA methylation for HNC diagnosis.

scholarly journals Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children

2020 ◽  
pp. 1-11
Author(s):  
Lorenza Dall’ Aglio ◽  
Jolien Rijlaarsdam ◽  
Rosa H. Mulder ◽  
Alexander Neumann ◽  
Janine F. Felix ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stress Responses ◽  
Association Studies ◽  
Maternal Sensitivity ◽  
Population Based ◽  
Epigenetic Mechanism ◽  
Developmental Problems ◽  
Maternal Caregiving ◽  
Typical Variation

Abstract Background Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment. Methods Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses. Results Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10−07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4. Conclusions These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

Abstract T P167: Emergent Identification of Type A Aortic Dissection as a Cause of Acute Ischemic Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Tomoyuki Ohara ◽  
Kazunori Toyoda ◽  
Hiroyuki Yokoyama ◽  
Kenji Minatoya ◽  
Eijiro Tanaka ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Back Pain ◽  
Cerebral Ischemia ◽  
Aortic Dissection ◽  
Intravenous Thrombolysis ◽  
Type A ◽  
Neurological Deficits ◽  
Diagnostic Tools ◽  
Acute Cerebral Ischemia ◽  
D Dimer

Background: Acute aortic dissection (AAD) sometimes presents with predominant neurological symptoms of acute cerebral ischemia. Fatal AAD patients after thrombolysis for stroke without noticing AAD were reported. The purpose of this study was to clarify the characteristics of AAD patients with acute cerebral ischemia and develop a score to emergently identify AAD for such patients. Methods: From the database of Stanford type A-AAD patients admitted in our hospital between 2007 and 2012, we selected those presenting with acute focal neurological deficits due to ischemic stroke/TIA. Patients presenting with shock state or cardiopulmonary arrest were excluded. Physiological, radiological, and blood examinations were assessed for AAD identification. Results: Of 187 AAD patients, 19 patients (10%) with focal neurological deficits as an initial presentation were studied. Involvement of one or more main branches of the aortic arch was observed in all of 19 patients. Stroke experts, not cardiovascular experts, were primarily called to ER in 18 patients, and 12 were potential candidates for intravenous thrombolysis. Left hemiparesis (14 patients, 74%) was the most common neurological symptom. Nine patients (47%) complained of chest or back pain. As components of the score, (1) systolic BP differential >20mmHg between upper extremities was present in 11 of 17 patients (65%), (2) mediastinal widening on chest radiography in 13/16 (81%), (3) occlusion or the intimal flap of the proximal common carotid artery on carotid ultrasonography in 14/16 (88%), (4) pericardial effusion on echocardiography in 10/19 (47%), and (5) abnormal elevation of D-dimer levels in all 19 (median 24.8 [range 4.2-406.2] μg/ml). Two components were positive in 4 patients, three in 6, four in 5, and all the five in 4. Conclusions: Only half of AAD patients with stroke/TIA complained of chest or back pain. All the AAD patients with stroke/TIA showed high D-dimer levels and one or more additional abnormal findings in physiological and radiological examinations. Combination of such handy diagnostic tools is helpful to identify AAD without long time delay and to avoid unnecessary thrombolysis for AAD patients.

scholarly journals Global DNA methylation was changed by a maternal high-lipid, high-energy diet during gestation and lactation in male adult mice liver

2015 ◽  
Vol 113 (7) ◽  
pp. 1032-1039 ◽  
Author(s):  
Huan-Ling Yu ◽  
Shan Dong ◽  
Li-Fang Gao ◽  
Li Li ◽  
Yuan-Di Xi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Maternal Diet ◽  
High Energy ◽  
Methylation Pattern ◽  
Epigenetic Mechanism ◽  
Chow Diet ◽  
Mrna Levels ◽  
Promoter Regions ◽  
Male Adult ◽  
High Lipid

An epigenetic mechanism has been suggested to explain the effects of the maternal diet on the development of disease in offspring. The present study aimed to observe the effects of a maternal high-lipid, high-energy (HLE) diet on the DNA methylation pattern of male offspring in mice. Female C57BL/6J mice were fed an HLE diet during gestation and lactation. The genomic DNA methylations at promoter sites of genes in the liver, mRNA and protein levels of selected genes related to lipid and glucose metabolism were measured by microarray, real-time PCR and Western blot. The results indicated that the percentage of methylated DNA in offspring from dams that were fed an HLE diet was significantly higher than that from dams that were fed a chow diet, and most of these genes were hypermethylated in promoter regions. The nuclear protein content and mRNA levels of hypermethylated genes, such as PPARγ and liver X receptor α (LXRα), were decreased significantly in offspring in the HLE group. The results suggested that the DNA methylation profile in adult offspring livers was changed by the maternal HLE diet during gestation and lactation.

scholarly journals Deciphering DNA Methylation in HIV Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Thilona Arumugam ◽  
Upasana Ramphal ◽  
Theolan Adimulam ◽  
Romona Chinniah ◽  
Veron Ramsuran
Keyword(s):  
Dna Methylation ◽  
Hiv Infection ◽  
Therapeutic Strategy ◽  
New Drugs ◽  
Sub Saharan Africa ◽  
Epigenetic Mechanism ◽  
People Living With Hiv ◽  
Modifying Factors ◽  
Autoimmune Conditions ◽  
Sub Saharan

With approximately 38 million people living with HIV/AIDS globally, and a further 1.5 million new global infections per year, it is imperative that we advance our understanding of all factors contributing to HIV infection. While most studies have focused on the influence of host genetic factors on HIV pathogenesis, epigenetic factors are gaining attention. Epigenetics involves alterations in gene expression without altering the DNA sequence. DNA methylation is a critical epigenetic mechanism that influences both viral and host factors. This review has five focal points, which examines (i) fluctuations in the expression of methylation modifying factors upon HIV infection (ii) the effect of DNA methylation on HIV viral genes and (iii) host genome (iv) inferences from other infectious and non-communicable diseases, we provide a list of HIV-associated host genes that are regulated by methylation in other disease models (v) the potential of DNA methylation as an epi-therapeutic strategy and biomarker. DNA methylation has also been shown to serve as a robust therapeutic strategy and precision medicine biomarker against diseases such as cancer and autoimmune conditions. Despite new drugs being discovered for HIV, drug resistance is a problem in high disease burden settings such as Sub-Saharan Africa. Furthermore, genetic therapies that are under investigation are irreversible and may have off target effects. Alternative therapies that are nongenetic are essential. In this review, we discuss the potential role of DNA methylation as a novel therapeutic intervention against HIV.

scholarly journals Creating and validating a DNA methylation-based proxy for Interleukin-6

2020 ◽  
Author(s):  
Anna J Stevenson ◽  
Danni A Gadd ◽  
Robert Francis Hillary ◽  
Daniel L. McCartney ◽  
Archie Campbell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cognitive Functioning ◽  
Cognitive Ability ◽  
Chronic Inflammation ◽  
Interleukin 6 ◽  
Epigenetic Mechanism ◽  
Inverse Association ◽  
Age Related ◽  
Independent Test ◽  
Methylation Score

Chronic inflammation is a pervasive feature of ageing and may be linked to age-related cognitive decline. However, population studies evaluating its relationship with cognitive functioning have produced heterogeneous results. A potential reason for this is the variability of inflammatory mediators which could lead to misclassifications of individuals' persisting levels of inflammation. The epigenetic mechanism DNA methylation has shown utility in indexing environmental exposures and could potentially be leveraged to provide proxy signatures of chronic inflammation. We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 895 older adults (mean age: 69 years) to develop a DNA methylation-based predictor. The predictor was tested in an independent cohort (n=7,028 [417 with measured IL-6], mean age: 51 years).We examined the association between the DNA methylation IL-6 score and serum IL-6, its association with age and established correlates of circulating IL-6, and with cognitive ability. A weighted score from 12 DNA methylation sites optimally predicted IL-6 (independent test set R2=5.1%). In the independent test cohort, both measured IL-6, and the DNA methylation proxy, increased as a function of age (serum IL-6: n=417, β=0.02, SE=0.004 p=1.3x10-7; DNAm IL-6 score: n=7,028, β=0.02, SE=0.0009, p<2x10-16). Serum IL-6 was not found to associate with cognitive ability (n=417, β=-0.06, SE=0.05, p=0.19); however, an inverse association was identified between the DNA methylation score and cognitive functioning (n=7,028, β=-0.14, SE=0.02, pFDR=1.5x10-14). These results suggest DNA methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for reliable insights into the relationship between chronic inflammation and pertinent health outcomes.

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