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Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 33275

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Special Issue Editors

Dr. Salvatore Fusco

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Guest Editor

Department of Neuroscience, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
Interests: nutrient-dependent signals; epigenetics; brain plasticity; neural stem cells

Prof. Dr. Maria Rita Rippo

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Guest Editor

Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
Interests: aging; apoptosis; autophagy; mesenchymal stem cells; Fas/FasL; microRNA; tumor; MeCP2; inflammaging; ganglioside

Special Issue Information

Dear Colleagues,

An increasing body of evidence indicates that epigenetic changes represent the molecular mechanisms underlying the impact of environmental stimuli on modulation of gene expression, whose alteration may lead to the development of human diseases.

Epigenetic changes consist of several molecular modifications to both DNA and chromatin, including DNA methylation and post-translational histone modifications that influence the chromatin packaging of DNA. Other epigenetic mechanisms regulating gene expression are represented by non-coding RNAs and the control of spatial organization of chromatin within the nucleus. All these factors are editable and are dynamically modified by external stimuli. Moreover, non-coding RNAs and proteins influencing chromatin remodelling may be transferred to other cells via extracellular vesicles, which represent a novel frontier of intercellular communication and short- or long-range epigenetic reprogramming of cellular fate.

Importantly, epigenetic changes can be stably maintained in somatic cells, causing long-term effects on gene expression. Indeed, early life exposure to environmental factors, such as chemical, nutritional and behavioural stimuli, can result in altered epigenetic landscape and increased risk of developing disease. In addition, epigenetic alterations might also be transgenerationally inherited, thereby potentially modulating health and vulnerability to diseases of next generations.

As life expectancy of the worldwide population increases, ageing and age-related disorders emerge as major issues for societies around the globe and epigenetic changes appear as critical factors modulating disease susceptibility. The primary focus of this special issue be the investigation and characterization of epigenetic mechanisms underlying the impact of environmental stimuli on physiological and pathophysiological ageing. In addition, the scientific contributes will delineate the novel frontiers of the research about the role of epigenome in the development of age-related diseases and as target of therapeutic approaches.

Dr. Salvatore Fusco
Prof. Dr. Maria Rippo
Guest Editors

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Keywords

epigenetics
ageing
age-related diseases
histone modifications
DNA methylation
non-coding RNAs

Published Papers (13 papers)

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Research

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15 pages, 2401 KiB

Open AccessArticle

Genome-Wide Methylation Changes Associated with Replicative Senescence and Differentiation in Endothelial and Bone Marrow Mesenchymal Stromal Cells

by Angelica Giuliani, Maria Giulia Bacalini, Deborah Ramini, Emanuela Mensà, Chiara Giordani, Luciano Xumerle, Paolo Garagnani, Fabiola Olivieri, Antonio Domenico Procopio, Maria Rita Rippo and Jacopo Sabbatinelli

Cells 2023, 12(2), 285; https://doi.org/10.3390/cells12020285 - 11 Jan 2023

Cited by 3 | Viewed by 1599

Abstract

Bone marrow mesenchymal stromal cells (BMSCs) are multipotent cells able to self-renew and differentiate, depending on the microenvironment, into adipocytes and osteoblasts. These cells have a limited number of replications and enter replicative senescence during in vitro expansion. The role of DNA methylation (DNAm) assumes importance in cell function and commitment; however, its exact contribution to BMSC differentiation and replicative senescence is still unclear. We performed a genome-wide DNAm analysis on BMSCs cultured in vitro at early passages and induced to differentiate into adipocytes and osteoblasts, and on replicative senescent BMSCs and HUVECs, to identify DNAm patterns of senescence and differentiation. We also compared BMSCs and HUVECs in replicative senescence and found that, in both cellular systems, genome-wide hypomethylation was accompanied by a higher-than-expected overlap of differentially methylated positions (DMPs) and concordance in terms of direction of the change. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on lineage-independent senescence-associated DMPs revealed 16 common pathways, including Insulin resistance, Molecule adhesion, and Wnt/β-catenin signaling. In both adipogenesis and osteogenesis, we observed a general demethylation of CpG sites compared with undifferentiated BMSCs with a higher number of DMPs in osteogenesis. KEGG analysis resulted in 30 pathways enriched in osteoblasts and only 2 in adipocytes when compared to undifferentiated cells. When comparing differentiated BMSCs with senescent ones, osteogenesis exhibited a greater overlap with senescence in terms of number of DMPs and direction of methylation change compared to adipogenesis. In conclusion, this study may be useful for future research on general mechanisms that occur in replicative senescence and furthermore to identify trajectories of BMSC differentiation and common aspects of differentiated and senescent cells. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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13 pages, 2255 KiB

Open AccessArticle

Maternal High Fat Diet Anticipates the AD-like Phenotype in 3xTg-AD Mice by Epigenetic Dysregulation of Aβ Metabolism

by Francesca Natale, Matteo Spinelli, Marco Rinaudo, Sara Cocco, Ida Nifo Sarrapochiello, Salvatore Fusco and Claudio Grassi

Cells 2023, 12(2), 220; https://doi.org/10.3390/cells12020220 - 4 Jan 2023

Cited by 1 | Viewed by 1852

Abstract

Maternal overnutrition has been reported to affect brain plasticity of the offspring by altering gene expression, regulating both synaptic plasticity and adult neurogenesis. However, whether perinatal metabolic stress may influence the accumulation of misfolded proteins and the development of neurodegeneration remains to be clarified. We investigated the impact of maternal high fat diet (HFD) in an experimental model of Alzheimer’s disease (AD). The 3xTg-AD mice born to overfed mothers showed an impairment of synaptic plasticity and cognitive deficits earlier than controls. Maternal HFD also altered the expression of genes regulating amyloid-β-protein (Aβ) metabolism (i.e., Bace1, Ern1, Ide and Nicastrin) and enhanced Aβ deposition in the hippocampus. Finally, we found an epigenetic derangement and an aberrant recruitment of transcription factors NF-kB and STAT3 and chromatin remodeler HDAC2 on the regulatory sequences of the same genes. Collectively, our data indicate that early life metabolic stress worsens the AD phenotype via epigenetic alteration of genes regulating Aβ synthesis and clearance. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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11 pages, 1573 KiB

Open AccessArticle

A Blood-Based Molecular Clock for Biological Age Estimation

by Ersilia Paparazzo, Silvana Geracitano, Vincenzo Lagani, Denise Bartolomeo, Mirella Aurora Aceto, Patrizia D’Aquila, Luigi Citrigno, Dina Bellizzi, Giuseppe Passarino and Alberto Montesanto

Cells 2023, 12(1), 32; https://doi.org/10.3390/cells12010032 - 21 Dec 2022

Cited by 1 | Viewed by 2513

Abstract

In the last decade, extensive efforts have been made to identify biomarkers of biological age. DNA methylation levels of ELOVL fatty acid elongase 2 (ELOVL2) and the signal joint T-cell receptor rearrangement excision circles (sjTRECs) represent the most promising candidates. Although these two non-redundant biomarkers echo important biological aspects of the ageing process in humans, a well-validated molecular clock exploiting these powerful candidates has not yet been formulated. The present study aimed to develop a more accurate molecular clock in a sample of 194 Italian individuals by re-analyzing the previously obtained EVOLV2 methylation data together with the amount of sjTRECs in the same blood samples. The proposed model showed a high prediction accuracy both in younger individuals with an error of about 2.5 years and in older subjects where a relatively low error was observed if compared with those reported in previously published studies. In conclusion, an easy, cost-effective and reliable model to measure the individual rate and the quality of aging in human population has been proposed. Further studies are required to validate the model and to extend its use in an applicative context. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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15 pages, 1222 KiB

Open AccessFeature PaperArticle

A Targeted Epigenetic Clock for the Prediction of Biological Age

by Noémie Gensous, Claudia Sala, Chiara Pirazzini, Francesco Ravaioli, Maddalena Milazzo, Katarzyna Malgorzata Kwiatkowska, Elena Marasco, Sara De Fanti, Cristina Giuliani, Camilla Pellegrini, Aurelia Santoro, Miriam Capri, Stefano Salvioli, Daniela Monti, Gastone Castellani, Claudio Franceschi, Maria Giulia Bacalini and Paolo Garagnani

Cells 2022, 11(24), 4044; https://doi.org/10.3390/cells11244044 - 14 Dec 2022

Cited by 10 | Viewed by 3323

Abstract

Epigenetic clocks were initially developed to track chronological age, but accumulating evidence indicates that they can also predict biological age. They are usually based on the analysis of DNA methylation by genome-wide methods, but targeted approaches, based on the assessment of a small number of CpG sites, are advisable in several settings. In this study, we developed a targeted epigenetic clock purposely optimized for the measurement of biological age. The clock includes six genomic regions mapping in ELOVL2, NHLRC1, AIM2, EDARADD, SIRT7 and TFAP2E genes, selected from a re-analysis of existing microarray data, whose DNA methylation is measured by EpiTYPER assay. In healthy subjects (n = 278), epigenetic age calculated using the targeted clock was highly correlated with chronological age (Spearman correlation = 0.89). Most importantly, and in agreement with previous results from genome-wide clocks, epigenetic age was significantly higher and lower than expected in models of increased (persons with Down syndrome, n = 62) and decreased (centenarians, n = 106; centenarians’ offspring, n = 143; nutritional intervention in elderly, n = 233) biological age, respectively. These results support the potential of our targeted epigenetic clock as a new marker of biological age and open its evaluation in large cohorts to further promote the assessment of biological age in healthcare practice. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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13 pages, 3125 KiB

Open AccessArticle

Replicative Senescence-Associated LINE1 Methylation and LINE1-Alu Expression Levels in Human Endothelial Cells

by Deborah Ramini, Silvia Latini, Angelica Giuliani, Giulia Matacchione, Jacopo Sabbatinelli, Emanuela Mensà, Maria Giulia Bacalini, Paolo Garagnani, Maria Rita Rippo, Giuseppe Bronte, Massimiliano Bonafè, Maurizio Cardelli and Fabiola Olivieri

Cells 2022, 11(23), 3799; https://doi.org/10.3390/cells11233799 - 27 Nov 2022

Cited by 3 | Viewed by 1876

Abstract

One of the main challenges of current research on aging is to identify the complex epigenetic mechanisms involved in the acquisition of the cellular senescent phenotype. Despite some evidence suggested that epigenetic changes of DNA repetitive elements, including transposable elements (TE) sequences, are associated with replicative senescence of fibroblasts, data on different types of cells are scarce. We previously analysed genome-wide DNA methylation of young and replicative senescent human endothelial cells (HUVECs), highlighting increased levels of demethylated sequences in senescent cells. Here, we aligned the most significantly demethylated single CpG sites to the reference genome and annotated their localization inside TE sequences and found a significant hypomethylation of sequences belonging to the Long-Interspersed Element-1 (LINE-1 or L1) subfamilies L1M, L1P, and L1HS. To verify the hypothesis that L1 demethylation could be associated with increased transcription/activation of L1s and/or Alu elements (non-autonomous retroelements that usually depend on L1 sequences for reverse transcription and retrotransposition), we quantified the RNA expression levels of both L1 (generic L1 elements or site-specific L1PA2 on chromosome 14) and Alu elements in young and senescent HUVECs and human dermal fibroblasts (NHDFs). The RNA expression of Alu and L1 sequences was significantly increased in both senescent HUVECs and NHDFs, whereas the RNA transcript of L1PA2 on chromosome 14 was not significantly modulated in senescent cells. Moreover, we found an increased amount of TE DNA copies in the cytoplasm of senescent HUVECs and NHDFs. Our results support the hypothesis that TE, which are significantly increased in senescent cells, could be retrotranscribed to DNA sequences. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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14 pages, 6837 KiB

Open AccessArticle

Epigenetic Changes within the Annulus Fibrosus by DNA Methylation in Rat Intervertebral Disc Degeneration Model

by Jin Young Hong, Hyunseong Kim, Wan-Jin Jeon, Junseon Lee, Changhwan Yeo, Yoon Jae Lee and In-Hyuk Ha

Cells 2022, 11(22), 3547; https://doi.org/10.3390/cells11223547 - 10 Nov 2022

Cited by 1 | Viewed by 1679

Abstract

Intervertebral disc degeneration (IDD) is an age-dependent progressive spinal disease that causes chronic back or neck pain. Although aging has long been presented as the main risk factor, the exact cause is not fully known. DNA methylation is associated with chronic pain, suggesting that epigenetic modulation may ameliorate disc degeneration. We examined histological changes in the DNA methylation within the discs and their association with pain-related transient receptor potential vanilloid subtype 1 (TrpV1) expression in rats subjected to IDD. Epigenetic markers (5-hydroxymethylcytosine (5hmC), 5-methylcytosine (5Mc)), DNA methyltransferases (DNMTs), and Ten-eleven translocations (Tets) were analyzed using immunohistochemistry, real-time PCR, and DNA dot-blot following IDD. Results revealed high 5mC levels in the annulus fibrosus (AF) region within the disc after IDD and an association with TrpV1 expression. DNMT1 is mainly involved in 5mC conversion in degenerated discs. However, 5hmC levels did not differ between groups. A degenerated disc can lead to locomotor defects as assessed by ladder and tail suspension tests, no pain signals in the von Frey test, upregulated matrix metalloproteinase-3, and downregulated aggrecan levels within the disc. Thus, we found that the DNA methylation status in the AF region of the disc was mainly changed after IDD and associated with aberrant TrpV1 expression in degenerated discs. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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14 pages, 9167 KiB

Open AccessArticle

High Fat Diet Multigenerationally Affects Hippocampal Neural Stem Cell Proliferation via Epigenetic Mechanisms

by Francesca Natale, Matteo Spinelli, Saviana Antonella Barbati, Lucia Leone, Salvatore Fusco and Claudio Grassi

Cells 2022, 11(17), 2661; https://doi.org/10.3390/cells11172661 - 27 Aug 2022

Cited by 8 | Viewed by 1792

Abstract

Early-life metabolic stress has been demonstrated to affect brain development, persistently influence brain plasticity and to exert multigenerational effects on cognitive functions. However, the impact of an ancestor’s diet on the adult neurogenesis of their descendants has not yet been investigated. Here, we studied the effects of maternal high fat diet (HFD) on hippocampal adult neurogenesis and the proliferation of neural stem and progenitor cells (NSPCs) derived from the hippocampus of both the second and the third generations of progeny (F2_HFD and F3_HFD). Maternal HFD caused a multigenerational depletion of neurogenic niche in F2_HFD and F3_HFD mice. Moreover, NSPCs derived from HFD descendants showed altered expression of genes regulating stem cell proliferation and neurodifferentiation (i.e., Hes1, NeuroD1, Bdnf). Finally, ancestor HFD-related hyper-activation of both STAT3 and STAT5 induced enhancement of their binding on the regulatory sequences of Gfap gene and an epigenetic switch from permissive to repressive chromatin on the promoter of the NeuroD1 gene. Collectively, our data indicate that maternal HFD multigenerationally affects hippocampal adult neurogenesis via an epigenetic derangement of pro-neurogenic gene expression in NSPCs. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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19 pages, 2642 KiB

Open AccessArticle

Differential Epigenetic Status and Responses to Stressors between Retinal Cybrids Cells with African versus European Mitochondrial DNA: Insights into Disease Susceptibilities

by Shari R. Atilano, Sina Abedi, Narcisa V. Ianopol, Mithalesh K. Singh, J Lucas Norman, Deepika Malik, Payam Falatoonzadeh, Marilyn Chwa, Anthony B. Nesburn, Baruch D. Kuppermann and M. Cristina Kenney

Cells 2022, 11(17), 2655; https://doi.org/10.3390/cells11172655 - 26 Aug 2022

Cited by 2 | Viewed by 1764

Abstract

Mitochondrial (mt) DNA can be classified into haplogroups, which represent populations with different geographic origins. Individuals of maternal African backgrounds (L haplogroup) are more prone to develop specific diseases compared those with maternal European-H haplogroups. Using a cybrid model, effects of amyloid-β (Amyβ), sub-lethal ultraviolet (UV) radiation, and 5-Aza-2′-deoxycytidine (5-aza-dC), a methylation inhibitor, were investigated. Amyβ treatment decreased cell metabolism and increased levels of reactive oxygen species in European-H and African-L cybrids, but lower mitochondrial membrane potential (ΔΨM) was found only in African-L cybrids. Sub-lethal UV radiation induced higher expression levels of CFH, EFEMP1, BBC3, and BCL2L13 in European-H cybrids compared to African-L cybrids. With respect to epigenetic status, the African-L cybrids had (a) 4.7-fold higher total global methylation levels (p = 0.005); (b) lower expression patterns for DNMT3B; and (c) elevated levels for HIST1H3F. The European-H and African-L cybrids showed different transcription levels for CFH, EFEMP1, CXCL1, CXCL8, USP25, and VEGF after treatment with 5-aza-dC. In conclusion, compared to European-H haplogroup cybrids, the African-L cybrids have different (i) responses to exogenous stressors (Amyβ and UV radiation), (ii) epigenetic status, and (iii) modulation profiles of methylation-mediated downstream complement, inflammation, and angiogenesis genes, commonly associated with various human diseases. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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19 pages, 1540 KiB

Open AccessArticle

Artificial Intelligence and Circulating Cell-Free DNA Methylation Profiling: Mechanism and Detection of Alzheimer’s Disease

by Ray O. Bahado-Singh, Uppala Radhakrishna, Juozas Gordevičius, Buket Aydas, Ali Yilmaz, Faryal Jafar, Khaled Imam, Michael Maddens, Kshetra Challapalli, Raghu P. Metpally, Wade H. Berrettini, Richard C. Crist, Stewart F. Graham and Sangeetha Vishweswaraiah

Cells 2022, 11(11), 1744; https://doi.org/10.3390/cells11111744 - 25 May 2022

Cited by 11 | Viewed by 4208

Abstract

Background: Despite extensive efforts, significant gaps remain in our understanding of Alzheimer’s disease (AD) pathophysiology. Novel approaches using circulating cell-free DNA (cfDNA) have the potential to revolutionize our understanding of neurodegenerative disorders. Methods: We performed DNA methylation profiling of cfDNA from AD patients and compared them to cognitively normal controls. Six Artificial Intelligence (AI) platforms were utilized for the diagnosis of AD while enrichment analysis was used to elucidate the pathogenesis of AD. Results: A total of 3684 CpGs were significantly (adj. p-value < 0.05) differentially methylated in AD versus controls. All six AI algorithms achieved high predictive accuracy (AUC = 0.949–0.998) in an independent test group. As an example, Deep Learning (DL) achieved an AUC (95% CI) = 0.99 (0.95–1.0), with 94.5% sensitivity and specificity. Conclusion: We describe numerous epigenetically altered genes which were previously reported to be differentially expressed in the brain of AD sufferers. Genes identified by AI to be the best predictors of AD were either known to be expressed in the brain or have been previously linked to AD. We highlight enrichment in the Calcium signaling pathway, Glutamatergic synapse, Hedgehog signaling pathway, Axon guidance and Olfactory transduction in AD sufferers. To the best of our knowledge, this is the first reported genome-wide DNA methylation study using cfDNA to detect AD. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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14 pages, 8236 KiB

Open AccessArticle

Histone H3 Lysine 4 and 27 Trimethylation Landscape of Human Alzheimer’s Disease

by Giuseppe Persico, Francesca Casciaro, Stefano Amatori, Martina Rusin, Francesco Cantatore, Amalia Perna, Lavinia Alberi Auber, Mirco Fanelli and Marco Giorgio

Cells 2022, 11(4), 734; https://doi.org/10.3390/cells11040734 - 19 Feb 2022

Cited by 12 | Viewed by 2873

Abstract

Background: Epigenetic remodeling is emerging as a critical process for both the onset and progression of Alzheimer’s disease (AD), the most common form of neurodegenerative dementia. However, it is not clear to what extent the distribution of histone modifications is involved in AD. Methods: To investigate histone H3 modifications in AD, we compared the genome-wide distributions of H3K4me3 and H3K27me3 in entorhinal cortices from severe sporadic AD patients and from age-matched healthy individuals of both sexes. Results: AD samples were characterized by typical average levels and distributions of the H3K4me3 and H3K27me3 signals. However, AD patients showed a lower H3K4me3 and higher H3K27me3 signal, particularly in males. Interestingly, the genomic sites found differentially trimethylated at the H3K4 between healthy and AD samples involve promoter regions of genes belonging to AD-related pathways such as glutamate receptor signaling. Conclusions: The signatures of H3K4me3 and H3K27me3 identified in AD patients validate the role of epigenetic chromatin remodeling in neurodegenerative disease and shed light on the genomic adaptive mechanisms involved in AD. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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12 pages, 653 KiB

Open AccessArticle

Species-Specific Paternal Age Effects and Sperm Methylation Levels of Developmentally Important Genes

by Andreas Prell, Mustafa Orkun Sen, Ramya Potabattula, Laura Bernhardt, Marcus Dittrich, Thomas Hahn, Martin Schorsch, Federica Zacchini, Grazyna Ewa Ptak, Heiner Niemann and Thomas Haaf

Cells 2022, 11(4), 731; https://doi.org/10.3390/cells11040731 - 19 Feb 2022

Cited by 8 | Viewed by 2643

Abstract

A growing number of sperm methylome analyses have identified genomic loci that are susceptible to paternal age effects in a variety of mammalian species, including human, bovine, and mouse. However, there is little overlap between different data sets. Here, we studied whether or not paternal age effects on the sperm epigenome have been conserved in mammalian evolution and compared methylation patterns of orthologous regulatory regions (mainly gene promoters) containing both conserved and non-conserved CpG sites in 94 human, 36 bovine, and 94 mouse sperm samples, using bisulfite pyrosequencing. We discovered three (NFKB2, RASGEF1C, and RPL6) age-related differentially methylated regions (ageDMRs) in humans, four (CHD7, HDAC11, PAK1, and PTK2B) in bovines, and three (Def6, Nrxn2, and Tbx19) in mice. Remarkably, the identified sperm ageDMRs were all species-specific. Most ageDMRs were in genomic regions with medium methylation levels and large methylation variation. Orthologous regions in species not showing this age effect were either hypermethylated (>80%) or hypomethylated (<20%). In humans and mice, ageDMRs lost methylation, whereas bovine ageDMRs gained methylation with age. Our results are in line with the hypothesis that sperm ageDMRs are in regions under epigenomic evolution and may be part of an epigenetic mechanism(s) for lineage-specific environmental adaptations and provide a solid basis for studies on downstream effects in the genes analyzed here. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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12 pages, 1131 KiB

Open AccessArticle

Association of FOXO3 Blood DNA Methylation with Cancer Risk, Cancer Survival, and Mortality

by Chenglong Yu, Allison M. Hodge, Ee Ming Wong, Jihoon Eric Joo, Enes Makalic, Daniel Schmidt, Daniel D. Buchanan, John L. Hopper, Graham G. Giles, Melissa C. Southey and Pierre-Antoine Dugué

Cells 2021, 10(12), 3384; https://doi.org/10.3390/cells10123384 - 1 Dec 2021

Cited by 7 | Viewed by 2419

Abstract

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case–control studies of breast (n = 409 cases), colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869), and urothelial (n = 428) cancer and B-cell lymphoma (n = 438). Case–control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality (n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60–3.56, p = 1.9 × 10⁻⁵). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival (p < 6.1 × 10⁻⁵). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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Review

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14 pages, 1856 KiB

Open AccessReview

The NuRD Complex in Neurodevelopment and Disease: A Case of Sliding Doors

by Paraskevi Boulasiki, Xiao Wei Tan, Matteo Spinelli and Antonella Riccio

Cells 2023, 12(8), 1179; https://doi.org/10.3390/cells12081179 - 18 Apr 2023

Cited by 2 | Viewed by 2904

Abstract

The Nucleosome Remodelling and Deacetylase (NuRD) complex represents one of the major chromatin remodelling complexes in mammalian cells, uniquely coupling the ability to “open” the chromatin by inducing nucleosome sliding with histone deacetylase activity. At the core of the NuRD complex are a family of ATPases named CHDs that utilise the energy produced by the hydrolysis of the ATP to induce chromatin structural changes. Recent studies have highlighted the prominent role played by the NuRD in regulating gene expression during brain development and in maintaining neuronal circuitry in the adult cerebellum. Importantly, components of the NuRD complex have been found to carry mutations that profoundly affect neurological and cognitive development in humans. Here, we discuss recent literature concerning the molecular structure of NuRD complexes and how the subunit composition and numerous permutations greatly determine their functions in the nervous system. We will also discuss the role of the CHD family members in an array of neurodevelopmental disorders. Special emphasis will be given to the mechanisms that regulate the NuRD complex composition and assembly in the cortex and how subtle mutations may result in profound defects of brain development and the adult nervous system. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms Underlying Ageing and Age-Related Diseases)

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