scholarly journals A DNAmRep epigenetic fingerprint for determining cellular replication age

2020 ◽  
Author(s):  
Christopher Minteer ◽  
Marco Morselli ◽  
Margarita Meer ◽  
Jian Cao ◽  
Sabine Lang ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Enrichment Analysis ◽  
T Antigen ◽  
Drug Induced ◽  
Chromatin Regulators ◽  
Biomarkers Of Aging ◽  
Epigenetic Aging ◽  
Passage Number ◽  
Cellular Replication ◽  
Aging Phenomena

AbstractAging is known to elicit dramatic changes to DNA methylation (DNAm). However, the causes and consequences of such alterations to the epigenome remain unclear. Therefore, the utility of biomarkers of aging based on DNAm patterns will depend on our ability to link them to cellular features, such as proliferation, differentiation, transcriptional repression/activation, senescence, and transformation. Using DNAm from serially passaged mouse embryonic fibroblasts (MEFs), we developed a predictor of replication that is able to accurately predict passage number in independent sample. Our measure, termed DNAmRep, was shown to strongly increase with age when examined in multiple tissues (blood, liver, kidney, lung and adipose). Furthermore, we observed replicative deceleration in animal undergoing caloric restriction. Upon reprogramming to iPSCs, cells derived from both lung and kidney fibroblasts exhibited resetting of our DNAmRep measure. This measure also increased in response to differentiation among B-cell populations. Enrichment analysis implicated CBX7, RNF2 and HDAC2 as potentially important transcription factors and chromatin regulators in the DNAm replication signature. Finally, DNAmRep correlated with beta-galactosidase activity in replicative senescent MEFs, but not in radiation or drug induced senescent MEFs, and was partially separated by immortalization with Large T antigen K1 mutant (LTK1), suggesting that it reflects mitotic history, rather than senescent state. Overall, this study identifies mitotically-derived alterations to the methylome, which partially underlie known epigenetic aging phenomena.

scholarly journals A DNAmCULTURE Epigenetic Fingerprint Recapitulates Physiological Aging

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 5-6
Author(s):  
Christopher Minteer ◽  
Marco Morselli ◽  
Margarita Meer ◽  
Jian Cao ◽  
Sabine Lang ◽  
...  
Keyword(s):  
Cultured Cells ◽  
In Vitro Models ◽  
Epigenetic Alterations ◽  
Physiological Aging ◽  
Biomarkers Of Aging ◽  
Epigenetic Aging ◽  
Passage Number ◽  
Aging Phenomena ◽  
Lung And Kidney

Abstract Aging elicits dramatic changes to DNA methylation (DNAm), however the causes and consequences of such alterations to the epigenome remain unclear. The utility of biomarkers of aging based on DNAm patterns would be greatly enhanced if in vitro models existed that recapitulated physiological phenotypes such that modulation could garnish mechanistic insights. Using DNAm from serially passaged mouse embryonic fibroblasts, we developed a marker of culture aging and asked if culture phenotypes, like exhaustive replication, are epigenetically analogous to physiological aging. Our measure, termed DNAmCULTURE, accurately estimated passage number and was shown to strongly increase with age when examined in multiple tissues. Furthermore, we observed epigenetic alterations indicative of early cultured cells in animals undergoing caloric restriction and in lung and kidney fibroblasts re-programmed to iPSCs. This study identifies culture-derived alterations to the methylome as physiologically relevant and implicates culture aging as an important feature in known epigenetic aging phenomena.

scholarly journals Pathway Interactions Based on Drug-Induced Datasets

2019 ◽  
Vol 18 ◽  
pp. 117693511985151 ◽  
Author(s):  
Shinuk Kim
Keyword(s):  
Breast Cancer ◽  
Valproic Acid ◽  
Epithelial Cells ◽  
Sample Size ◽  
Drug Combination ◽  
Trichostatin A ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Drug Induced

In this study, we identified enrichment pathway connections from MCF7 breast cancer epithelial cells that were treated with 87 drugs. We extracted drug-treated samples, where the sample size was greater than or equal to 5. The drugs included 17-allylamino-geldanamycin, LY294002, trichostatin A, valproic acid, sirolimus, and wortmannin, which had sample sizes of 11, 8, 7, 7, 7, and 5, respectively. We found meaningful pathways using gene set enrichment analysis and identified intradrug and interdrug pathway interactions, which implied the influence of drug combination. Among the top 20 enrichment pathways that were wortmannin induced, there were a total of 37 intradrug pathway interactions via common genes. Thirty-seven pathway interactions were induced by valproic acid, 11 induced by trichostatin A, 20 induced by LY294002, and 59 induced by sirolimus, all via common genes. The number of interdrug-induced pathway interactions ranged from one pair of pathways to 23. The pair of ERBB_SIGNALING and INSULIN_SIGNALING pathways showed the highest score from a pair of 2 individual drugs. The highest number of pathway interactions was observed between the drugs 17-allylamino-geldanamycin and LY294002.

scholarly journals Pair bonding slows epigenetic aging and alters methylation in brains of prairie voles

2020 ◽  
Author(s):  
Lindsay L. Sailer ◽  
Amin Haghani ◽  
Joseph A. Zoller ◽  
Caesar Z. Li ◽  
Alexander G. Ophir ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Tissue ◽  
Association Studies ◽  
Chronological Age ◽  
Epigenetic Clock ◽  
Pair Bonding ◽  
Prairie Voles ◽  
Relative Age ◽  
Biomarkers Of Aging ◽  
Epigenetic Aging

ABSTRACTThe quality of romantic relationships can be predictive of health consequences related to aging. DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how pair bonding impacts aging. Prairie voles (Microtus ochrogaster) have emerged as a model to study social attachment among adult pairs. Here we describe DNA methylation-based estimators of age for prairie voles based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for voles was trained on 3 tissue sources (ear, liver, and samples of brain tissue from within the pair bonding circuit). A novel dual species human-vole clock accurately measured relative age defined as the ratio of chronological age to maximum age. According to the human-vole clock of relative age, sexually inexperienced voles exhibit accelerated epigenetic aging in brain tissue (p = 0.02) when compared to pair bonded animals of the same chronological age. Epigenome wide association studies identified CpGs in four genes that were strongly associated with pair bonding across the three tissue types (brain, ear, and liver): Hnrnph1, Fancl, Fam13b, and Fzd1. Further, four CpGs (near the Bmp4 exon, Eif4g2 3 prime UTR, Robo1 exon, and Nfat5 intron) exhibited a convergent methylation change between pair bonding and aging. This study describes highly accurate DNA methylation-based estimators of age in prairie voles and provides evidence that pair bonding status modulates the methylome.

scholarly journals Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain

2021 ◽  
Vol 12 ◽  
Author(s):  
Feitong Shi ◽  
Yudan He ◽  
Yao Chen ◽  
Xinman Yin ◽  
Xianzheng Sha ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Extracellular Fluid ◽  
Accelerated Aging ◽  
Enrichment Analysis ◽  
Supervised Machine Learning ◽  
System Level ◽  
Aging Brain ◽  
Cellular Homeostasis ◽  
Epigenetic Aging ◽  
Aging Mechanisms

Background: Neurodegenerative Diseases (NDs) are age-dependent and include Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and so on. There have been numerous studies showing that accelerated aging is closely related (even the driver of) ND, thus promoting imbalances in cellular homeostasis. However, the mechanisms of how different ND types are related/triggered by advanced aging are still unclear. Therefore, there is an urgent need to explore the potential markers/mechanisms of different ND types based on aging acceleration at a system level.Methods: AD, PD, PSP, FTD, and aging markers were identified by supervised machine learning methods. The aging acceleration differential networks were constructed based on the aging score. Both the enrichment analysis and sensitivity analysis were carried out to investigate both common and specific mechanisms among different ND types in the context of aging acceleration.Results: The extracellular fluid, cellular metabolisms, and inflammatory response were identified as the common driving factors of cellular homeostasis imbalances during the accelerated aging process. In addition, Ca ion imbalance, abnormal protein depositions, DNA damage, and cytoplasmic DNA in macrophages were also revealed to be special mechanisms that further promote AD, PD, PSP, and FTD, respectively.Conclusion: The accelerated epigenetic aging mechanisms of different ND types were integrated and compared through our computational pipeline.

scholarly journals Transcriptional repression of the E2-containing promoters EIIaE, c-myc, and RB1 by the product of the RB1 gene.

1992 ◽  
Vol 12 (8) ◽  
pp. 3431-3438 ◽  
Author(s):  
P A Hamel ◽  
R M Gill ◽  
R A Phillips ◽  
B L Gallie
Keyword(s):  
Cell Cycle ◽  
Transcriptional Repression ◽  
Susceptibility Gene ◽  
Protein Product ◽  
T Antigen ◽  
Binding Motif ◽  
Regulation Of Transcription ◽  
Expression Of Genes ◽  
Cellular Genes ◽  
A Cell

The protein product of the retinoblastoma susceptibility gene, p110RB1, is a nuclear phosphoprotein [W.H. Lee, J.Y. Shew, F.D. Hong, T.W. Sery, L.A. Donoso, L.J. Young, R. Bookstein, and E.Y. Lee, Nature (London) 329:642-645, 1987] with properties of a cell cycle regulator (K. Buchkovich, L.A. Duffy, and E. Harlow, Cell 58:1097-1105, 1989; P.L. Chen, P. Scully, J.Y. Shew, J.Y. Wang, and W.H. Lee, Cell 58:1193-1198, 1989; J.A. DeCaprio, J.W. Ludlow, D. Lynch, Y. Furukawa, J. Griffin, H. Piwnica-Worms, C.M. Huang, and D.M. Livingston, Cell 58:1085-1095, 1989; and K. Mihara, X.R. Cao, A. Yen, S. Chandler, B. Driscoll, A.L. Murphree, A. TAng, and Y.K. Fung, Science 246:1300-1303, 1989). Although the mechanism of action of p110RB1 remains unknown, several lines of evidence suggest that it plays a role in the regulation of transcription. We now show that overexpression of p110RB1 causes repression of the adenovirus early promoter EIIaE and the promoters of two cellular genes, c-myc and RB1, both of which contain E2F-binding motifs. Mutation of the E2 element in the c-myc promoter abolishes p110RB1 repression. We also demonstrate that a p110RB1 mutant, which is refractory to cell cycle phosphorylation but intact in E1a/large T antigen-binding properties, represses EIIaE with 50- to 80-fold greater efficiency than wild-type p110RB1. These data provide evidence that hypophosphorylated p110RB1 actively represses expression of genes with promoters containing the E2F-binding motif (E2 element).

scholarly journals Dissecting the Transcriptomes of Multiple Metronidazole-Resistant and Sensitive Trichomonas vaginalis Strains Identified Distinct Genes and Pathways Associated with Drug Resistance and Cell Death

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1817
Author(s):  
Po-Jung Huang ◽  
Ching-Yun Huang ◽  
Yu-Xuan Li ◽  
Yi-Chung Liu ◽  
Lichieh-Julie Chu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Trichomonas Vaginalis ◽  
Regulatory Networks ◽  
Efflux Pump ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Multidrug Efflux Pump ◽  
Drug Induced ◽  
Transmitted Infection

Trichomonas vaginalis is the causative agent of trichomoniasis, the most prevalent non-viral sexually transmitted infection worldwide. Metronidazole (MTZ) is the mainstay of anti-trichomonal chemotherapy; however, drug resistance has become an increasingly worrying issue. Additionally, the molecular events of MTZ-induced cell death in T. vaginalis remain elusive. To gain insight into the differential expression of genes related to MTZ resistance and cell death, we conducted RNA-sequencing of three paired MTZ-resistant (MTZ-R) and MTZ-sensitive (MTZ-S) T. vaginalis strains treated with or without MTZ. Comparative transcriptomes analysis identified that several putative drug-resistant genes were exclusively upregulated in different MTZ-R strains, such as ATP-binding cassette (ABC) transporters and multidrug resistance pumps. Additionally, several shared upregulated genes among all the MTZ-R transcriptomes were not previously identified in T. vaginalis, such as 5′-nucleotidase surE and Na+-driven multidrug efflux pump, which are a potential stress response protein and a multidrug and toxic compound extrusion (MATE)-like protein, respectively. Functional enrichment analysis revealed that purine and pyrimidine metabolisms were suppressed in MTZ-S parasites upon drug treatment, whereas the endoplasmic reticulum-associated degradation (ERAD) pathway, proteasome, and ubiquitin-mediated proteolysis were strikingly activated, highlighting the novel pathways responsible for drug-induced stress. Our work presents the most detailed analysis of the transcriptional changes and the regulatory networks associated with MTZ resistance and MTZ-induced signaling, providing insights into MTZ resistance and cell death mechanisms in trichomonads.

scholarly journals Electrospun Scaffold Micro-Architecture Induces an Activated Transcriptional Phenotype within Tendon Fibroblasts

2022 ◽  
Vol 9 ◽  
Author(s):  
Mathew J. Baldwin ◽  
Jolet Y. Mimpen ◽  
Adam P. Cribbs ◽  
Edward Stace ◽  
Martin Philpott ◽  
...  
Keyword(s):  
Rotator Cuff ◽  
Inflammatory Responses ◽  
Large Diameter ◽  
Transcriptional Response ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Type Iii Collagen ◽  
Tissue Remodelling ◽  
Cellular Replication ◽  
Cellular Phenotypes

Biomaterial augmentation of surgically repaired rotator cuff tendon tears aims to improve the high failure rates (∼40%) of traditional repairs. Biomaterials that can alter cellular phenotypes through the provision of microscale topographical cues are now under development. We aimed to systematically evaluate the effect of topographic architecture on the cellular phenotype of fibroblasts from healthy and diseased tendons. Electrospun polydioxanone scaffolds with fiber diameters ranging from 300 to 4000 nm, in either a highly aligned or random configuration, were produced. Healthy tendon fibroblasts cultured for 7 days on scaffolds with highly aligned fibers demonstrated a distinctive elongated morphology, whilst those cultured on randomly configured fibers demonstrated a flattened and spread morphology. The effect of scaffold micro-architecture on the transcriptome of both healthy and diseased tendon fibroblasts was assessed with bulk RNA-seq. Both healthy (n = 3) and diseased tendon cells (n = 3) demonstrated a similar transcriptional response to architectural variants. Gene set enrichment analysis revealed that large diameter (≥2000 nm) aligned scaffolds induced an upregulation of genes involved in cellular replication and a downregulation of genes defining inflammatory responses and cell adhesion. Similarly, PDPN and CD248, markers of inflammatory or “activated” fibroblasts, were downregulated during culture of both healthy and diseased fibroblasts on aligned scaffolds with large (≥2000 nm) fiber diameters. In conclusion scaffold architectures resembling that of disordered type III collagen, typically present during the earlier phases of wound healing, resulted in tendon fibroblast activation. Conversely, scaffolds mimicking aligned diameter collagen I fibrils, present during tissue remodelling, did not activate tendon derived fibroblasts. This has implications for the design of scaffolds used during rotator cuff repair augmentation.

scholarly journals Reversing age: dual species measurement of epigenetic age with a single clock

2020 ◽  
Author(s):  
Steve Horvath ◽  
Kavita Singh ◽  
Ken Raj ◽  
Shraddha Khairnar ◽  
Akshay Sanghavi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Training Data ◽  
Rat Tissues ◽  
Epigenetic Clock ◽  
Tissue Samples ◽  
Beneficial Effects ◽  
Biomarkers Of Aging ◽  
Plasma Fraction ◽  
Epigenetic Aging ◽  
Epigenetic Age

AbstractYoung blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

Transcriptional repression of the E2-containing promoters EIIaE, c-myc, and RB1 by the product of the RB1 gene

1992 ◽  
Vol 12 (8) ◽  
pp. 3431-3438
Author(s):  
P A Hamel ◽  
R M Gill ◽  
R A Phillips ◽  
B L Gallie
Keyword(s):  
Cell Cycle ◽  
Transcriptional Repression ◽  
Susceptibility Gene ◽  
Protein Product ◽  
T Antigen ◽  
Binding Motif ◽  
Regulation Of Transcription ◽  
Expression Of Genes ◽  
Cellular Genes ◽  
A Cell

The protein product of the retinoblastoma susceptibility gene, p110RB1, is a nuclear phosphoprotein [W.H. Lee, J.Y. Shew, F.D. Hong, T.W. Sery, L.A. Donoso, L.J. Young, R. Bookstein, and E.Y. Lee, Nature (London) 329:642-645, 1987] with properties of a cell cycle regulator (K. Buchkovich, L.A. Duffy, and E. Harlow, Cell 58:1097-1105, 1989; P.L. Chen, P. Scully, J.Y. Shew, J.Y. Wang, and W.H. Lee, Cell 58:1193-1198, 1989; J.A. DeCaprio, J.W. Ludlow, D. Lynch, Y. Furukawa, J. Griffin, H. Piwnica-Worms, C.M. Huang, and D.M. Livingston, Cell 58:1085-1095, 1989; and K. Mihara, X.R. Cao, A. Yen, S. Chandler, B. Driscoll, A.L. Murphree, A. TAng, and Y.K. Fung, Science 246:1300-1303, 1989). Although the mechanism of action of p110RB1 remains unknown, several lines of evidence suggest that it plays a role in the regulation of transcription. We now show that overexpression of p110RB1 causes repression of the adenovirus early promoter EIIaE and the promoters of two cellular genes, c-myc and RB1, both of which contain E2F-binding motifs. Mutation of the E2 element in the c-myc promoter abolishes p110RB1 repression. We also demonstrate that a p110RB1 mutant, which is refractory to cell cycle phosphorylation but intact in E1a/large T antigen-binding properties, represses EIIaE with 50- to 80-fold greater efficiency than wild-type p110RB1. These data provide evidence that hypophosphorylated p110RB1 actively represses expression of genes with promoters containing the E2F-binding motif (E2 element).

scholarly journals Human Papillomavirus Type 16 E7 Oncoprotein Associates with E2F6

2008 ◽  
Vol 82 (17) ◽  
pp. 8695-8705 ◽  
Author(s):  
Margaret E. McLaughlin-Drubin ◽  
Kyung-Won Huh ◽  
Karl Münger
Keyword(s):  
Human Papillomavirus ◽  
Cell Fate ◽  
Transcriptional Repression ◽  
Defense Mechanism ◽  
Simian Virus 40 ◽  
T Antigen ◽  
S Phase ◽  
Polycomb Group ◽  
Keratinocyte Differentiation ◽  
Hpv E7

ABSTRACT The papillomavirus life cycle is intimately coupled to the differentiation state of the infected epithelium. Since papillomaviruses lack most of the rate-limiting enzymes required for genome synthesis, they need to uncouple keratinocyte differentiation from cell cycle arrest and maintain or reestablish a replication-competent state within terminally differentiated keratinocytes. The human papillomavirus (HPV) E7 protein appears to be a major determinant for this activity and induces aberrant S-phase entry through the inactivation of the retinoblastoma tumor suppressor and related pocket proteins. In addition, E7 can abrogate p21 and p27. Together, this leads to the activation of E2F1 to E2F5, enhanced expression of E2F-responsive genes, and increased cdk2 activity. E2F6 is a pRB-independent, noncanonical member of the E2F transcription factor family that acts as a transcriptional repressor. E2F6 expression is activated in S phase through an E2F-dependent mechanism and thus may provide a negative-feedback mechanism that slows down S-phase progression and/or exit in response to the activation of the other E2F transcription factors. Here, we show that low- and high-risk HPV E7 proteins, as well as simian virus 40 T antigen and adenovirus E1A, can associate with and inactivate the transcriptional repression activity of E2F6, thereby subverting a critical cellular defense mechanism. This may result in the extended S-phase competence of HPV-infected cells. E2F6 is a component of polycomb group complexes, which bind to silenced chromatin and are critical for the maintenance of cell fate. We show that E7-expressing cells show decreased staining for E2F6/polycomb complexes and that this is at least in part dependent on the association with E2F6.

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