87 results on '"Beck, Stephan"'
Search Results
2. An improved epigenetic counter to track mitotic age in normal and precancerous tissues.
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Zhu, Tianyu, Tong, Huige, Du, Zhaozhen, Beck, Stephan, and Teschendorff, Andrew E.
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PRECANCEROUS conditions ,DNA methylation ,DISEASE risk factors ,EPIGENETICS ,CELL division - Abstract
The cumulative number of stem cell divisions in a tissue, known as mitotic age, is thought to be a major determinant of cancer-risk. Somatic mutational and DNA methylation (DNAm) clocks are promising tools to molecularly track mitotic age, yet their relationship is underexplored and their potential for cancer risk prediction in normal tissues remains to be demonstrated. Here we build and validate an improved pan-tissue DNAm counter of total mitotic age called stemTOC. We demonstrate that stemTOC's mitotic age proxy increases with the tumor cell-of-origin fraction in each of 15 cancer-types, in precancerous lesions, and in normal tissues exposed to major cancer risk factors. Extensive benchmarking against 6 other mitotic counters shows that stemTOC compares favorably, specially in the preinvasive and normal-tissue contexts. By cross-correlating stemTOC to two clock-like somatic mutational signatures, we confirm the mitotic-like nature of only one of these. Our data points towards DNAm as a promising molecular substrate for detecting mitotic-age increases in normal tissues and precancerous lesions, and hence for developing cancer-risk prediction strategies. DNA methylation (DNAm) clocks can track mitotic age, but their potential use for cancer risk prediction remains less explored. Here, the authors develop a DNAm counter of total mitotic age (stemTOC) that shows an increase of mitotic age in normal tissues and precancerous lesions. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Donor whole blood DNA methylation is not a strong predictor of acute graft versus host disease in unrelated donor allogeneic haematopoietic cell transplantation.
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Webster, Amy P., Ecker, Simone, Moghul, Ismail, Xiaohong Liu, Dhami, Pawan, Marzi, Sarah, Paul, Dirk S., Kuxhausen, Michelle, Lee, Stephanie J., Spellman, Stephen R., Tao Wang, Feber, Andrew, Rakyan, Vardhman, Peggs, Karl S., and Beck, Stephan
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GRAFT versus host disease ,CELL transplantation ,DNA methylation ,HEMATOPOIETIC stem cell transplantation ,MACHINE learning ,CD30 antigen ,CREATININE - Abstract
Allogeneic hematopoietic cell transplantation (HCT) is used to treat many bloodbased disorders and malignancies, however it can also result in serious adverse events, such as the development of acute graft-versus-host disease (aGVHD). This study aimed to develop a donor-specific epigenetic classifier to reduce incidence of aGVHD by improving donor selection. Genome-wide DNA methylation was assessed in a discovery cohort of 288 HCT donors selected based on recipient aGVHD outcome; this cohort consisted of 144 cases with aGVHD grades III-IV and 144 controls with no aGVHD. We applied a machine learning algorithm to identify CpG sites predictive of aGVHD. Receiver operating characteristic (ROC) curve analysis of these sites resulted in a classifier with an encouraging area under the ROC curve (AUC) of 0.91. To test this classifier, we used an independent validation cohort (n = 288) selected using the same criteria as the discovery cohort. Attempts to validate the classifier failed with the AUC falling to 0.51. These results indicate that donor DNA methylation may not be a suitable predictor of aGVHD in an HCT setting involving unrelated donors, despite the initial promising results in the discovery cohort. Our work highlights the importance of independent validation of machine learning classifiers, particularly when developing classifiers intended for clinical use. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Open access-enabled evaluation of epigenetic age acceleration in colorectal cancer and development of a classifier with diagnostic potential.
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Widayati, Tyas Arum, Schneider, Jadesada, Panteleeva, Kseniia, Chernysheva, Elizabeth, Hrbkova, Natalie, Beck, Stephan, Voloshin, Vitaly, and Chervova, Olga
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COLORECTAL cancer ,CARCINOGENESIS ,EPIGENETICS ,TRAINING of scientists ,AGE ,ADENOMATOUS polyps - Abstract
Aberrant DNA methylation (DNAm) is known to be associated with the aetiology of cancer, including colorectal cancer (CRC). In the past, the availability of open access data has been the main driver of innovative method development and research training. However, this is increasingly being eroded by the move to controlled access, particularly of medical data, including cancer DNAm data. To rejuvenate this valuable tradition, we leveraged DNAm data from 1,845 samples (535 CRC tumours, 522 normal colon tissues adjacent to tumours, 72 colorectal adenomas, and 716 normal colon tissues from healthy individuals) from 14 open access studies deposited in NCBI GEO and ArrayExpress. We calculated each sample's epigenetic age (EA) using eleven epigenetic clock models and derived the corresponding epigenetic age acceleration (EAA). For EA, we observed that most first- and second-generation epigenetic clocks reflect the chronological age in normal tissues adjacent to tumours and healthy individuals [e.g., Horvath (r = 0.77 and 0.79), Zhang elastic net (EN) (r = 0.70 and 0.73)] unlike the epigenetic mitotic clocks (EpiTOC, HypoClock, MiAge) (r < 0.3). For EAA, we used PhenoAge, Wu, and the above mitotic clocks and found them to have distinct distributions in different tissue types, particularly between normal colon tissues adjacent to tumours and cancerous tumours, as well as between normal colon tissues adjacent to tumours and normal colon tissue from healthy individuals. Finally, we harnessed these associations to develop a classifier using elastic net regression (with lasso and ridge regularisations) that predicts CRC diagnosis based on a patient's sex and EAAs calculated from histologically normal controls (i.e., normal colon tissues adjacent to tumours and normal colon tissue from healthy individuals). The classifier demonstrated good diagnostic potential with ROC-AUC = 0.886, which suggests that an EAA-based classifier trained on relevant data could become a tool to support diagnostic/prognostic decisions in CRC for clinical professionals. Our study also reemphasises the importance of open access clinical data for method development and training of young scientists. Obtaining the required approvals for controlled access data would not have been possible in the timeframe of this study. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Points-to-consider on the return of results in epigenetic research
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Dyke, Stephanie O. M., Saulnier, Katie M., Dupras, Charles, Webster, Amy P., Maschke, Karen, Rothstein, Mark, Siebert, Reiner, Walter, Jörn, Beck, Stephan, Pastinen, Tomi, and Joly, Yann
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- 2019
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6. Associations between salivary DNA methylation and war exposure in Syrian refugee children and adolescents
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Smeeth, Demelza, McEwen, Fiona, Popham, Cassandra, Ecker, Simone, Beck, Stephan, Binder, Elisabeth, Karam, Elie, and Pluess, Michael
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DNA methylation ,epigenetics ,Medicine and Health Sciences ,Life Sciences ,war ,Social and Behavioral Sciences ,adversity ,epigenetic aging - Abstract
We examine whether salivary DNA methylation is associated with exposure to war in a child and adolescent cohort.
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- 2022
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7. Loss of the crumbs cell polarity complex disrupts epigenetic transcriptional control and cell cycle progression in the developing retina.
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Owen, Nicholas, Toms, Maria, Tian, Yuan, Toualbi, Lyes, Richardson, Rose, Young, Rodrigo, Tracey‐White, Dhani, Dhami, Pawan, Beck, Stephan, and Moosajee, Mariya
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CELL polarity ,BONE morphogenetic proteins ,TRANSFORMING growth factors ,EPIGENETICS ,SMAD proteins ,RECESSIVE genes ,CELL cycle - Abstract
The crumbs cell polarity complex plays a crucial role in apical–basal epithelial polarity, cellular adhesion, and morphogenesis. Homozygous variants in human CRB1 result in autosomal recessive Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP), with no established genotype–phenotype correlation. The associated protein complexes have key functions in developmental pathways; however, the underlying disease mechanism remains unclear. Using the oko meduzym289/m289 (crb2a−/−) zebrafish, we performed integrative transcriptomic (RNA‐seq data) and methylomic [reduced representation bisulphite sequencing (RRBS)] analysis of whole retina to identify dysregulated genes and pathways. Delayed retinal cell specification was identified in both the crb2a−/− zebrafish and CRB1 patient‐derived retinal organoids, highlighting the dysfunction of cell cycle modulation and epigenetic transcriptional control. Differential DNA methylation analysis revealed novel hypermethylated pathways involving biological adhesion, Hippo, and transforming growth factor β (TGFβ) signalling. By integrating gene expression with DNA methylation using functional epigenetic modules (FEM), we identified six key modules involving cell cycle control and disturbance of TGFβ, bone morphogenetic protein (BMP), Hippo, and SMAD protein signal transduction pathways, revealing significant interactome hotspots relevant to crb2a function and confirming the epigenetic control of gene regulation in early retinal development, which points to a novel mechanism underlying CRB1‐retinopathies. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Increased DNA methylation variability in rheumatoid arthritis-discordant monozygotic twins
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Webster, Amy P., Plant, Darren, Ecker, Simone, Zufferey, Flore, Bell, Jordana T., Feber, Andrew, Paul, Dirk S., Beck, Stephan, Barton, Anne, Williams, Frances M. K., and Worthington, Jane
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- 2018
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9. Evaluation of Epigenetic Age Acceleration Scores and Their Associations with CVD-Related Phenotypes in a Population Cohort.
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Chervova, Olga, Chernysheva, Elizabeth, Panteleeva, Kseniia, Widayati, Tyas Arum, Hrbkova, Natalie, Schneider, Jadesada, Maximov, Vladimir, Ryabikov, Andrew, Tillmann, Taavi, Pikhart, Hynek, Bobak, Martin, Voloshin, Vitaly, Malyutina, Sofia, and Beck, Stephan
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PHENOTYPES ,AGE ,EPIGENETICS ,CORONARY disease ,ATHEROSCLEROTIC plaque - Abstract
Simple Summary: We consider a subset (n = 306) of an Eastern European ageing population cohort which was followed up for 15 years. Using blood DNA methylation data, we calculated nine epigenetic age acceleration scores, which are defined as deviations of epigenetic age from chronological age. We then evaluated how those scores are associated with available phenotypic data. This was implemented by splitting the phenotypic data into groups with positive and negative epigenetic age acceleration, and evaluating the difference between those groups. We observed strong association between all the considered epigenetic age acceleration and sex, suggesting that any analysis of these scores should be adjusted for sex. Moreover, even after adjusting for sex, the associations between the scores and considered phenotypes remain sex-specific. The only two associations that persisted through the entire dataset and both male and female subsets are incident coronary heart disease and smoking status. The observed associations of the various epigenetic age acceleration scores with both individual and groups of phenotypes suggest that these scores are sensitive to various cardiometabolic parameters, which might indicate their prognostic potential for related disorders. We evaluated associations between nine epigenetic age acceleration (EAA) scores and 18 cardiometabolic phenotypes using an Eastern European ageing population cohort richly annotated for a diverse set of phenotypes (subsample, n = 306; aged 45–69 years). This was implemented by splitting the data into groups with positive and negative EAAs. We observed strong association between all EAA scores and sex, suggesting that any analysis of EAAs should be adjusted by sex. We found that some sex-adjusted EAA scores were significantly associated with several phenotypes such as blood levels of gamma-glutamyl transferase and low-density lipoprotein, smoking status, annual alcohol consumption, multiple carotid plaques, and incident coronary heart disease status (not necessarily the same phenotypes for different EAAs). We demonstrated that even after adjusting EAAs for sex, EAA–phenotype associations remain sex-specific, which should be taken into account in any downstream analysis involving EAAs. The obtained results suggest that in some EAA–phenotype associations, negative EAA scores (i.e., epigenetic age below chronological age) indicated more harmful phenotype values, which is counterintuitive. Among all considered epigenetic clocks, GrimAge was significantly associated with more phenotypes than any other EA scores in this Russian sample. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs
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Steegenga, Wilma T., Boekschoten, Mark V., Lute, Carolien, Hooiveld, Guido J., de Groot, Philip J., Morris, Tiffany J., Teschendorff, Andrew E., Butcher, Lee M., Beck, Stephan, and Müller, Michael
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- 2014
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11. Immunogenomics: Molecular hide and seek
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Miretti Marcos M and Beck Stephan
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immunogenomics ,immunogenetics ,major histocompatibility complex (MHC) ,recombination ,linkage disequilibrium ,epigenetics ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Similar to other classical science disciplines, immunology has been embracing novel technologies and approaches giving rise to specialised sub-disciplines such as immunogenetics and, more recently, immunogenomics, which, in many ways, is the genome-wide application of immunogenetic approaches. Here, recent progress in the understanding of the immune sub-genome will be reviewed, and the ways in which immunogenomic datasets consisting of genetic and epigenetic variation, linkage disequilibrium and recombination can be harnessed for disease association and evolutionary studies will be discussed. The discussion will focus on data available for the major histocompatibility complex and the leukocyte receptor complex, the two most polymorphic regions of the human immune sub-genome.
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- 2006
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12. Epigenome-wide association studies for cancer biomarker discovery in circulating cell-free DNA: technical advances and challenges
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Tanić, Miljana and Beck, Stephan
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Epigenomics ,0301 basic medicine ,Biology ,Bioinformatics ,medicine.disease_cause ,03 medical and health sciences ,Neoplasms ,Biomarkers, Tumor ,Genetics ,medicine ,Humans ,Epigenetics ,Biomarker discovery ,Genetic association ,Genome, Human ,Cancer ,Genomics ,Epigenome ,medicine.disease ,Circulating Cell-Free DNA ,3. Good health ,030104 developmental biology ,Circulating DNA ,Carcinogenesis ,Cell-Free Nucleic Acids ,Developmental Biology - Abstract
Since introducing the concept of epigenome-wide association studies (EWAS) in 2011, there has been a vast increase in the number of published EWAS studies in common diseases, including in cancer. These studies have increased our understanding of epigenetic events underlying carcinogenesis and have enabled the discovery of cancer-specific methylation biomarkers. In this mini-review, we have focused on the state of the art in EWAS applied to cell-free circulating DNA for epigenetic biomarker discovery in cancer and discussed associated technical advances and challenges, and our expectations for the future of the field.
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- 2017
13. DNA Methylome Alterations Are Associated with Airway Macrophage Differentiation and Phenotype during Lung Fibrosis.
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McErlean, Peter, Bell, Christopher G., Hewitt, Richard J., Busharat, Zabreen, Ogger, Patricia P., Ghai, Poonam, Albers, Gesa J., Calamita, Emily, Kingston, Shaun, Molyneaux, Philip L., Beck, Stephan, Lloyd, Clare M., Maher, Toby M., and Byrne, Adam J.
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DNA methylation ,AIRWAY (Anatomy) ,MACROPHAGES ,PULMONARY fibrosis ,PHENOTYPES ,MYELOID cells - Abstract
Rationale: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge about the epigenetics of AMs in IPF is limited. Objectives: To assess the role of epigenetic regulation of AMs during lung fibrosis. Methods: We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors (n = 14) and donors with IPF (n = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Measurements and Main Results: Our analysis revealed that epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions (n = 11) and differentially methylated regions (n = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Conclusions: Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung. [ABSTRACT FROM AUTHOR]
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- 2021
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14. Opto-epigenetic modulation of DNA methylation with a photo-responsive small-molecule approach
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Mao, Shiqing, Nguyen, Ha, Stewart, Sabrina, Kukwikila, Mikiembo, Jones, Sioned, Offenbartl-Stiegert, Daniel, Beck, Stephan, Howorka, Stefan, Balasubramanian, Shankar, Balasubramanian, Shankar [0000-0002-0281-5815], and Apollo - University of Cambridge Repository
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photo-caging ,epigenetics ,Humans ,DNA ,methylation ,DNA Methylation ,cytosine ,Epigenesis, Genetic - Abstract
Controlling the functional dynamics of DNA within living cells is essential in biomedical research. Epigenetic modifications such as DNA methylation play a key role in this process. Controlled DNA methylation editing can be attained via genetic means. Yet there are few chemical tools available for the spatial and temporal modulation of this modification. Here we present a small-molecule approach to modulate DNA methylation with light. The strategy uses a photo-tuneable version of a clinically used drug (5-aza-2-deoxycytidine) to alter the catalytic activity of DNA methyltransferases, the enzymes that methylate DNA. After uptake by cells, the photo-regulated molecule can be light-controlled to reduce genome-wide DNA methylation levels in proliferating cells. The chemical tool complements genetic, biochemical and pharmacological approaches to study the role of DNA methylation in biology and medicine.
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- 2019
15. "Epigenome-wide methylation profile of chronic kidney disease-derived arterial DNA uncovers novel pathways in disease-associated cardiovascular pathology.".
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Dritsoula, Athina, Kislikova, Maria, Oomatia, Amin, Webster, Amy P., Beck, Stephan, Ponticos, Markella, Lindsey, Ben, Norman, Jill, Wheeler, David C., Oates, Thomas, and Caplin, Ben
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METHYLATION ,KIDNEY diseases ,CHRONIC kidney failure ,PATHOLOGY ,GENE expression - Abstract
Chronic kidney disease (CKD) related cardiovascular disease (CVD) is characterized by vascular remodelling with well-established structural and functional changes in the vascular wall such as arterial stiffness, matrix deposition, and calcification. These phenotypic changes resemble pathology seen in ageing, and are likely to be mediated by sustained alterations in gene expression, which may be caused by epigenetic changes such as tissue-specific DNA methylation. We aimed to investigate tissue specific changes in DNA methylation that occur in CKD-related CVD. Genome-wide DNA methylation changes were examined in bisulphite converted genomic DNA isolated from the vascular media of CKD and healthy arteries. Methylation-specific PCR was used to validate the array data, and the association between DNA methylation and gene and protein expression was examined. The DNA methylation age was compared to the chronological age in both cases and controls. Three hundred and nineteen differentially methylated regions (DMR) were identified spread across the genome. Pathway analysis revealed that DMRs associated with genes were involved in embryonic and vascular development, and signalling pathways such as TGFβ and FGF. Expression of top differentially methylated gene HOXA5 showed a significant negative correlation with DNA methylation. Interestingly, DNA methylation age and chronological age were highly correlated, but there was no evidence of accelerated age-related DNA methylation in the arteries of CKD patients. In conclusion, we demonstrated that differential DNA methylation in the arterial tissue of CKD patients represents a potential mediator of arterial pathology and may be used to uncover novel pathways in the genesis of CKD-associated complications. [ABSTRACT FROM AUTHOR]
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- 2021
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16. Resources for methylome analysis suitable for gene knockout studies of potential epigenome modifiers
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Wilson Gareth A, Dhami Pawandeep, Feber Andrew, Cortázar Daniel, Suzuki Yuka, Schulz Reiner, Schär Primo, and Beck Stephan
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Methylome ,MeDIP-seq ,Epigenetics ,Epigenomics ,DNA methylation ,Computational pipeline ,MeDUSA ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
Abstract Background Methylated DNA immunoprecipitation (MeDIP) is a popular enrichment based method and can be combined with sequencing (termed MeDIP-seq) to interrogate the methylation status of cytosines across entire genomes. However, quality control and analysis of MeDIP-seq data have remained to be a challenge. Results We report genome-wide DNA methylation profiles of wild type (wt) and mutant mouse cells, comprising 3 biological replicates of Thymine DNA glycosylase (Tdg) knockout (KO) embryonic stem cells (ESCs), in vitro differentiated neural precursor cells (NPCs) and embryonic fibroblasts (MEFs). The resulting 18 methylomes were analysed with MeDUSA (Methylated DNA Utility for Sequence Analysis), a novel MeDIP-seq computational analysis pipeline for the identification of differentially methylated regions (DMRs). The observed increase of hypermethylation in MEF promoter-associated CpG islands supports a previously proposed role for Tdg in the protection of regulatory regions from epigenetic silencing. Further analysis of genes and regions associated with the DMRs by gene ontology, pathway, and ChIP analyses revealed further insights into Tdg function, including an association of TDG with low-methylated distal regulatory regions. Conclusions We demonstrate that MeDUSA is able to detect both large-scale changes between cells from different stages of differentiation and also small but significant changes between the methylomes of cells that only differ in the KO of a single gene. These changes were validated utilising publicly available datasets and confirm TDG's function in the protection of regulatory regions from epigenetic silencing.
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- 2012
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17. UroMark-a urinary biomarker assay for the detection of bladder cancer
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Feber, Andrew, Dhami, Pawan, Dong, Liqin, De Winter, Patricia, Tan, Wei Shen, Martínez-Fernández, Mónica, Paul, Dirk S, Hynes-Allen, Antony, Rezaee, Sheida, Gurung, Pratik, Rodney, Simon, Mehmood, Ahmed, Villacampa, Felipe, De La Rosa, Federico, Jameson, Charles, Cheng, Kar Keung, Zeegers, Maurice P, Bryan, Richard T, James, Nicholas D, Paramio, Jesus M, Freeman, Alex, Beck, Stephan, Kelly, John D, RS: CAPHRI - R5 - Optimising Patient Care, Complexe Genetica, Feber, Andrew [0000-0001-5282-0498], and Apollo - University of Cambridge Repository
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Adult ,Male ,CARCINOMA ,5-AMINOLEVULINIC ACID ,Urine ,Epigenesis, Genetic ,Young Adult ,MARKERS ,Next generation sequencing ,SURVEILLANCE ,MANAGEMENT ,Biomarkers, Tumor ,Humans ,Diagnostic ,RECURRENCE ,Early Detection of Cancer ,Aged ,Aged, 80 and over ,Research ,LARGE-SCALE ,Bladder cancer ,High-Throughput Nucleotide Sequencing ,DNA, Neoplasm ,Sequence Analysis, DNA ,DNA Methylation ,Middle Aged ,CYSTOSCOPY ,Urinary Bladder Neoplasms ,HEMATURIA ,Epigenetics ,CpG Islands ,Female - Abstract
Background Bladder cancer (BC) is one of the most common cancers in the western world and ranks as the most expensive to manage, due to the need for cystoscopic examination. BC shows frequent changes in DNA methylation, and several studies have shown the potential utility of urinary biomarkers by detecting epigenetic alterations in voided urine. The aim of this study is to develop a targeted bisulfite next-generation sequencing assay to diagnose BC from urine with high sensitivity and specificity. Results We defined a 150 CpG loci biomarker panel from a cohort of 86 muscle-invasive bladder cancers and 30 normal urothelium. Based on this panel, we developed the UroMark assay, a next-generation bisulphite sequencing assay and analysis pipeline for the detection of bladder cancer from urinary sediment DNA. The 150 loci UroMark assay was validated in an independent cohort (n = 274, non-cancer (n = 167) and bladder cancer (n = 107)) voided urine samples with an AUC of 97%. The UroMark classifier sensitivity of 98%, specificity of 97% and NPV of 97% for the detection of primary BC was compared to non-BC urine. Conclusions Epigenetic urinary biomarkers for detection of BC have the potential to revolutionise the management of this disease. In this proof of concept study, we show the development and utility of a novel high-throughput, next-generation sequencing-based biomarker for the detection of BC-specific epigenetic alterations in urine. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0303-5) contains supplementary material, which is available to authorized users.
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- 2018
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18. oxBS-450K: A method for analysing hydroxymethylation using 450K BeadChips
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Stewart, Sabrina K., Morris, Tiffany J., Guilhamon, Paul, Bulstrode, Harry, Bachman, Martin, Balasubramanian, Shankar, and Beck, Stephan
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Epigenomics ,DNA methylation ,Biochemistry, Genetics and Molecular Biology(all) ,Hydroxymethylation ,Reproducibility of Results ,Sequence Analysis, DNA ,Bisulfite conversion ,450K BeadChip ,Article ,Oxidation ,Humans ,Epigenetics ,Molecular Biology ,Oligonucleotide Array Sequence Analysis - Abstract
Highlights • A method is presented for 5hmC detection and analysis using Infinium 450K BeadChips. • The oxBS-450K method can discriminate between 5mC and 5hmC in human gDNA • 5hmC levels were quantified genome-wide in 3 distinct biological samples. • The reported 5hmC signal was validated using mass spectrometry and pyrosequencing. • The effects of differing amounts of input DNA on final 5hmC call rate are discussed., DNA methylation analysis has become an integral part of biomedical research. For high-throughput applications such as epigenome-wide association studies, the Infinium HumanMethylation450 (450K) BeadChip is currently the platform of choice. However, BeadChip processing relies on traditional bisulfite (BS) based protocols which cannot discriminate between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Here, we report the adaptation of the recently developed oxidative bisulfite (oxBS) chemistry to specifically detect both 5mC and 5hmC in a single workflow using 450K BeadChips, termed oxBS-450K. Supported by validation using mass spectrometry and pyrosequencing, we demonstrate reproducible (R2 > 0.99) detection of 5hmC in human brain tissue using the optimised oxBS-450K protocol described here.
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- 2015
19. UroMark—a urinary biomarker assay for the detection of bladder cancer
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Feber, Andrew, Dhami, Pawan, Dong, Liqin, de Winter, Patricia, Tan, Wei Shen, Martínez-Fernández, Mónica, Paul, Dirk S., Hynes-Allen, Antony, Rezaee, Sheida, Gurung, Pratik, Rodney, Simon, Mehmood, Ahmed, Villacampa, Felipe, de la Rosa, Federico, Jameson, Charles, Cheng, Kar Keung, Zeegers, Maurice P., Bryan, Richard T., James, Nicholas D., Paramio, Jesus M., Freeman, Alex, Beck, Stephan, and Kelly, John D.
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RC0254 ,Next generation sequencing ,Bladder cancer ,Epigenetics ,Diagnostic ,Urine - Abstract
Background: Bladder cancer (BC) is one of the most common cancers in the western world and ranks as the most expensive to manage, due to the need for cystoscopic examination. BC shows frequent changes in DNA methylation, and several studies have shown the potential utility of urinary biomarkers by detecting epigenetic alterations in voided urine. The aim of this study is to develop a targeted bisulfite next-generation sequencing assay to diagnose BC from urine with high sensitivity and specificity.Results: We defined a 150 CpG loci biomarker panel from a cohort of 86 muscle-invasive bladder cancers and 30 normal urothelium. Based on this panel, we developed the UroMark assay, a next-generation bisulphite sequencing assay and analysis pipeline for the detection of bladder cancer from urinary sediment DNA. The 150 loci UroMark assay was validated in an independent cohort (n = 274, non-cancer (n = 167) and bladder cancer (n = 107)) voided urine samples with an AUC of 97%. The UroMark classifier sensitivity of 98%, specificity of 97% and NPV of 97% for the detection of primary BC was compared to non-BC urine.Conclusions: Epigenetic urinary biomarkers for detection of BC have the potential to revolutionise the management of this disease. In this proof of concept study, we show the development and utility of a novel high-throughput, next-generation sequencing-based biomarker for the detection of BC-specific epigenetic alterations in urine.
- Published
- 2017
20. Quantification of tumour evolution and heterogeneity via Bayesian epiallele detection
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Barrett, James E., Feber, Andrew, Herrero, Javier, Tanic, Miljana, Wilson, Gareth A., Swanton, Charles, and Beck, Stephan
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Epigenomics ,Lung Neoplasms ,Mathematics - Statistics Theory ,Statistics Theory (math.ST) ,lcsh:Computer applications to medicine. Medical informatics ,Quantitative Biology - Quantitative Methods ,Signalling & Oncogenes ,Ecology,Evolution & Ethology ,FOS: Mathematics ,Humans ,Quantitative Biology - Genomics ,lcsh:QH301-705.5 ,Alleles ,Quantitative Methods (q-bio.QM) ,Computational & Systems Biology ,Chemical Biology & High Throughput ,Genomics (q-bio.GN) ,Human Biology & Physiology ,Methodology Article ,Genome Integrity & Repair ,Bayes Theorem ,DNA Methylation ,Tumour Biology ,Phylogenetics ,lcsh:Biology (General) ,FOS: Biological sciences ,lcsh:R858-859.7 ,CpG Islands ,Epigenetics ,Heterogeneity ,Genetics & Genomics ,Algorithms - Abstract
Background Epigenetic heterogeneity within a tumour can play an important role in tumour evolution and the emergence of resistance to treatment. It is increasingly recognised that the study of DNA methylation (DNAm) patterns along the genome – so-called ‘epialleles’ – offers greater insight into epigenetic dynamics than conventional analyses which examine DNAm marks individually. Results We have developed a Bayesian model to infer which epialleles are present in multiple regions of the same tumour. We apply our method to reduced representation bisulfite sequencing (RRBS) data from multiple regions of one lung cancer tumour and a matched normal sample. The model borrows information from all tumour regions to leverage greater statistical power. The total number of epialleles, the epiallele DNAm patterns, and a noise hyperparameter are all automatically inferred from the data. Uncertainty as to which epiallele an observed sequencing read originated from is explicitly incorporated by marginalising over the appropriate posterior densities. The degree to which tumour samples are contaminated with normal tissue can be estimated and corrected for. By tracing the distribution of epialleles throughout the tumour we can infer the phylogenetic history of the tumour, identify epialleles that differ between normal and cancer tissue, and define a measure of global epigenetic disorder. Conclusions Detection and comparison of epialleles within multiple tumour regions enables phylogenetic analyses, identification of differentially expressed epialleles, and provides a measure of epigenetic heterogeneity. R code is available at github.com/james-e-barrett. Electronic supplementary material The online version of this article (doi:10.1186/s12859-017-1753-2) contains supplementary material, which is available to authorized users.
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- 2017
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21. Differentiation therapy for glioblastoma – too many obstacles?
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Carén, Helena, Beck, Stephan, and Pollard, Steven M.
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neural stem cell ,DNA methylation ,epigenetics ,BMP ,differentiation ,Astrocyte ,Glioblastoma ,Author's View ,oligodendrocyte - Abstract
The therapeutic potential of differentiation therapy for glioblastoma will depend on the robustness and stability of the differentiated state. We recently reported several obstacles to bone morphogenetic protein (BMP)-induced differentiation therapy. Improved understanding of the mechanisms that tumor cells use to escape differentiation commitment is urgently needed.
- Published
- 2015
22. A Photo‐responsive Small‐Molecule Approach for the Opto‐epigenetic Modulation of DNA Methylation.
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Nguyen, Ha Phuong, Stewart, Sabrina, Kukwikila, Mikiembo N., Jones, Sioned Fôn, Offenbartl‐Stiegert, Daniel, Mao, Shiqing, Balasubramanian, Shankar, Beck, Stephan, and Howorka, Stefan
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DNA methylation ,DEOXYRIBOZYMES ,CATALYTIC activity ,DNA ,METHYLTRANSFERASES ,MEDICAL research - Abstract
Controlling the functional dynamics of DNA within living cells is essential in biomedical research. Epigenetic modifications such as DNA methylation play a key role in this endeavour. DNA methylation can be controlled by genetic means. Yet there are few chemical tools available for the spatial and temporal modulation of this modification. Herein, we present a small‐molecule approach to modulate DNA methylation with light. The strategy uses a photo‐tuneable version of a clinically used drug (5‐aza‐2′‐deoxycytidine) to alter the catalytic activity of DNA methyltransferases, the enzymes that methylate DNA. After uptake by cells, the photo‐regulated molecule can be light‐controlled to reduce genome‐wide DNA methylation levels in proliferating cells. The chemical tool complements genetic, biochemical, and pharmacological approaches to study the role of DNA methylation in biology and medicine. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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- View/download PDF
23. Tracking the Epigenetic Clock Across the Human Life Course: A Meta-analysis of Longitudinal Cohort Data.
- Author
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Marioni, Riccardo E, Suderman, Matthew, Chen, Brian H, Horvath, Steve, Bandinelli, Stefania, Morris, Tiffany, Beck, Stephan, Ferrucci, Luigi, Pedersen, Nancy L, Relton, Caroline L, Deary, Ian J, and Hägg, Sara
- Subjects
EPIGENETICS ,DNA methylation ,AGE distribution ,LONGEVITY ,LONGITUDINAL method - Abstract
Background: Epigenetic clocks based on DNA methylation yield high correlations with chronological age in cross-sectional data. Due to a paucity of longitudinal data, it is not known how Δage (epigenetic age - chronological age) changes over time or if it remains constant from childhood to old age. Here, we investigate this using longitudinal DNA methylation data from five datasets, covering most of the human life course.Methods: Two measures of the epigenetic clock (Hannum and Horvath) are used to calculate Δage in the following cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) offspring (n = 986, total age-range 7-19 years, 2 waves), ALSPAC mothers (n = 982, 16-60 years, 2 waves), InCHIANTI (n = 460, 21-100 years, 2 waves), SATSA (n = 373, 48-99 years, 5 waves), Lothian Birth Cohort 1936 (n = 1,054, 70-76 years, 3 waves), and Lothian Birth Cohort 1921 (n = 476, 79-90 years, 3 waves). Linear mixed models were used to track longitudinal change in Δage within each cohort.Results: For both epigenetic age measures, Δage showed a declining trend in almost all of the cohorts. The correlation between Δage across waves ranged from 0.22 to 0.82 for Horvath and 0.25 to 0.71 for Hannum, with stronger associations in samples collected closer in time.Conclusions: Epigenetic age increases at a slower rate than chronological age across the life course, especially in the oldest population. Some of the effect is likely driven by survival bias, where healthy individuals are those maintained within a longitudinal study, although other factors like the age distribution of the underlying training population may also have influenced this trend. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
24. Epigenetic and Transcriptional Variability Shape Phenotypic Plasticity.
- Author
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Ecker, Simone, Pancaldi, Vera, Valencia, Alfonso, Beck, Stephan, and Paul, Dirk S.
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EPIGENETICS ,PHENOTYPIC plasticity ,GENOTYPE-environment interaction ,INDIVIDUALIZED medicine ,PREVENTIVE medicine - Abstract
Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. In this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. We highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. Further, we provide an overview of challenges in the analysis of biological variability. An improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra‐ and inter‐individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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25. DNA methylome analysis reveals distinct epigenetic patterns of ascending aortic dissection and bicuspid aortic valve.
- Author
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Sun Pan, Hao Lai, Yiru Shen, Charles Breeze, Beck, Stephan, Tao Hong, Chunsheng Wang, and Teschendorff, Andrew E.
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DNA analysis ,EPIGENETICS ,AORTIC dissection ,AORTIC valve ,DNA methylation ,GENE expression ,MUSCLE cells ,ASCENDING aorta dissection - Abstract
Aims Epigenetics may mediate the effects of environmental risk factors on disease, including heart disease. Thus, measuring the DNA methylome offers the opportunity to identify novel disease biomarkers and novel insights into disease mechanisms. The DNA methylation landscape of ascending aortic dissection (AD) and bicuspid aortic valve (BAV) with aortic aneurysmal dilatation remain uncharacterized. The present study aimed to explore the genome-wide DNA methylation landscape underpinning these two diseases. Methods and results We used Illumina 450k DNA methylation beadarrays to analyse 21 ascending aorta samples, including 10 cases with AD, 5 with BAV and 6 healthy controls. We adjusted for intra-sample cellular heterogeneity, providing the first unbiased genome-wide exploration of the DNA methylation landscape underpinning these two diseases. We discover that both diseases are characterized by loss of DNA methylation at non-CpG sites. We validate this non- CpG hypomethylation signature with pyrosequencing. In contrast to non-CpGs, AD and BAV exhibit distinct DNA methylation landscapes at CpG sites, with BAV characterized mainly by hypermethylation of EZH2 targets. In the case of AD, integrative DNA methylation gene expression analysis reveals that AD is characterized by a dedifferentiated smooth muscle cell phenotype. Our integrative analysis further reveals hypomethylation associated overexpression of RARA in AD, a pattern which is also seen in cells exposed to smoke toxins. Conclusion Our data supports a model in which increased cellular proliferation in AD and BAV underpins loss of methylation at non-CpG sites. Our data further supports a model, in which AD is associated with an inflammatory vascular remodeling process, possibly mediated by the epigenome and linked to environmental risk factors such as smoking. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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- View/download PDF
26. Validation of the MethylationEPIC BeadChip for fresh-frozen and formalin-fixed paraffin-embedded tumours.
- Author
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Kling, Teresia, Wenger, Anna, Beck, Stephan, and Carén, Helena
- Subjects
DNA methylation ,EPIGENETICS ,GENE expression - Abstract
DNA methylation is the most studied epigenetic modification due to its role in regulating gene expression, and its involvement in the pathogenesis of cancer and several diseases upon aberrations in methylation. The method of choice to evaluate genome-wide methylation has been the Illumina HumanMethylation450 BeadChip (450K), but it was recently replaced with the MethylationEPIC BeadChip (EPIC). We therefore sought to validate the EPIC array in comparison to the 450K array for both fresh-frozen (FF) and formalin-fixed paraffin-embedded (FFPE) tumours. We also performed analysis on the EPIC array with paired FF and FFPE samples to adapt to a clinical setting where FFPE is routinely used. Further, we compared two restoration methods, REPLI-g and Infinium, for FFPE-derived DNA on the EPIC array. The Pearson correlation of ß values for common probes on the 450K and EPIC array was high for both FF (mean: 0.992) and FFPE (mean: 0.984) samples. The ß values generated from the EPIC array for FFPE samples correlated well with the paired FF tumours, but varied between 0.901 and 0.987. We did note that sample pairs with lower correlation had less bimodal density distributions of ß values and displayed higher noise in the copy number alteration plots (generated from the methylation array data) in the FFPE sample. Both REPLI-g and the Infinium restoration for FFPE samples performed well on the EPIC array and generated equivalent correlation scores to the paired FF sample. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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27. Progressive epigenetic dysregulation in neuroendocrine tumour liver metastases.
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Karpathakis, Anna, Dibra, Harpreet, Pipinikas, Christodoulos, Feber, Andrew, Morris, Tiffany, Francis, Joshua, Oukrif, Dahmane, Mandair, Dalvinder, Pericleous, Marinos, Mohmaduvesh, Mullan, Serra, Stefano, Ogunbiyi, Olagunju, Novelli, Marco, TuVinh Luong, Asa, Sylvia L., Kulke, Matthew, Toumpanakis, Christos, Meyer, Tim, Caplin, Martyn, and Beck, Stephan
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EPIGENETICS ,NEUROENDOCRINE tumors ,LIVER metastasis ,GENETIC mutation ,DNA copy number variations - Published
- 2017
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28. CORALINA: a universal method for the generation of gRNA libraries for CRISPR-based screening.
- Author
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Köferle, Anna, Worf, Karolina, Breunig, Christopher, Baumann, Valentin, Herrero, Javier, Wiesbeck, Maximilian, Hutter, Lukas H., Götz, Magdalena, Fuchs, Christiane, Beck, Stephan, and Stricker, Stefan H.
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CRISPRS ,RNA ,GENETIC engineering ,EPIGENETICS ,OLIGONUCLEOTIDE synthesis ,DNA - Abstract
Background: The bacterial CRISPR system is fast becoming the most popular genetic and epigenetic engineering tool due to its universal applicability and adaptability. The desire to deploy CRISPR-based methods in a large variety of species and contexts has created an urgent need for the development of easy, time- and cost-effective methods enabling large-scale screening approaches. Results: Here we describe CORALINA (comprehensive gRNA library generation through controlled nuclease activity), a method for the generation of comprehensive gRNA libraries for CRISPR-based screens. CORALINA gRNA libraries can be derived from any source of DNA without the need of complex oligonucleotide synthesis. We show the utility of CORALINA for human and mouse genomic DNA, its reproducibility in covering the most relevant genomic features including regulatory, coding and non-coding sequences and confirm the functionality of CORALINA generated gRNAs. Conclusions: The simplicity and cost-effectiveness make CORALINA suitable for any experimental system. The unprecedented sequence complexities obtainable with CORALINA libraries are a necessary pre-requisite for less biased large scale genomic and epigenomic screens. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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29. Genome-wide methylation profiling identifies novel methylated genes in neuroblastoma tumors.
- Author
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Olsson, Maja, Beck, Stephan, Kogner, Per, Martinsson, Tommy, and Carén, Helena
- Published
- 2016
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30. A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell transplantation.
- Author
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Paul, Dirk S., Jones, Allison, Sellar, Rob S., Mayor, Neema P., Feber, Andrew, Webster, Amy P., Afonso, Neuza, Sergeant, Ruhena, Szydlo, Richard M., Apperley, Jane F., Widschwendter, Martin, Mackinnon, Stephen, Marsh, Steven G. E., Madrigal, J. Alejandro, Rakyan, Vardhman K., Peggs, Karl S., and Beck, Stephan
- Subjects
EPIGENETICS ,GRAFT versus host disease ,HEMATOPOIETIC stem cell transplantation ,HLA histocompatibility antigens ,DNA methylation ,T cells - Abstract
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. Here, we investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in human leukocyte antigen (HLA)-matched sibling recipients prior to T cell-depleted HSCT. Methods: We measured DNA methylation levels genome-wide at single-nucleotide resolution in peripheral blood of 85 HSCT donors, matched to recipients with various transplant outcomes, with Illumina Infinium HumanMethylation450 BeadChips. Results: Using genome-wide DNA methylation profiling, we showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We discovered 31 DNA methylation marks in donors that associated with aGVHD severity status in recipients, and demonstrated strong predictive performance of these markers in internal cross-validation experiments (AUC = 0.98, 95 % CI = 0.96-0.99). We replicated the top-ranked CpG classifier using an alternative, clinical DNA methylation assay (P = 0.039). In an independent cohort of 32 HSCT donors, we demonstrated the utility of the epigenetic classifier in the context of a T cell-replete conditioning regimen (P = 0.050). Conclusions: Our findings suggest that epigenetic typing of HSCT donors in a clinical setting may be used in conjunction with HLA genotyping to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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31. Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome.
- Author
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Libertini, Emanuele, Lebreton, Alice, Lakisic, Goran, Dillies, Marie-Agnès, Beck, Stephan, Coppée, Jean-Yves, Cossart, Pascale, and Bierne, Hélène
- Subjects
HETEROCHROMATIN ,X chromosome ,EPIGENESIS - Abstract
BAH domain-containing protein 1 (BAHD1) is involved in heterochromatin formation and gene repression in human cells. BAHD1 also localizes to the inactive X chromosome (Xi), but the functional significance of this targeting is unknown. So far, research on this protein has been hampered by its low endogenous abundance and its role in epigenetic regulation remains poorly explored. In this work, we used whole-genome bisulfite sequencing (BS-seq) to compare the DNA methylation profile of HEK293 cells expressing low levels of BAHD1 (HEK-CT) to that of isogenic cells stably overexpressing BAHD1 (HEK-BAHD1). We show that increasing BAHD1 levels induces de novo DNA methylation on autosomes and a marked hypomethylation on the X chromosome (chrX). We identified 91,358 regions that have different methylation patterns in HEK-BAHD1 compared to HEK-CT cells (termed "BAHD1-DMRs"), of which 83,850 mapped on autosomes and 7508 on the X chromosome (chrX). Autosomal BAHD1-DMRs were predominantly hypermethylated and located to satellites, interspersed repeats, and intergenic regions. In contrast, BAHD1-DMRs on chrX were mainly hypomethylated and located to gene bodies and enhancers. We further found that BAHD1-DMRs display a higher-order organization by being clustered within large chromosomal domains. Half of these "BAHD1-Associated differentially methylated Domains" (BADs) overlapped with lamina-associated domains (LADs). Based on these results, we propose that BAHD1-mediated heterochromatin formation is linked to DNA methylation and may play a role in the spatial architecture of the genome. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
32. Analysis of the Polycomb-related lncRNAs HOTAIR and ANRIL in bladder cancer.
- Author
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Martínez-Fernández, Mónica, Feber, Andrew, Dueñas, Marta, Segovia, Cristina, Rubio, Carolina, Fernandez, Maria, Villacampa, Felipe, Duarte, José, López-Calderón, Fernando F., Gómez-Rodriguez, Ma José, Castellano, Daniel, Rodriguez-Peralto, Jose L., de la Rosa, Federico, Beck, Stephan, and Paramio, Jesús M.
- Subjects
NON-coding RNA ,BLADDER cancer ,GENE expression - Abstract
Background: Long non-coding RNAs (lncRNAs) have been claimed as key molecular players in gene expression regulation, being involved in diverse epigenetic processes. They are aberrantly expressed in various tumors, but their exact role in bladder cancer is still obscure. We have recently found a major role of the Polycomb repression complex in recurrence of non-muscle-invasive bladder cancer. Here, we report the xpression of Polycomb-related lncRNAs:antisense noncoding RNA in the INK4 locus (ANRIL) and HOX antisense intergenic RNA (HOTAIR) in these tumors. Findings: We studied a dataset of non-invasive bladder cancer samples by quantitative reverse transcription PCR (RT-qPCR) and analyzed also invasive bladder cancer samples using TCGA data. Our results showed that, while ANRIL seemed not to have a determining role, an increased HOTAIR expression appeared in recurrent and high-graded tumors associated with poor prognosis. In addition, through genome-wide transcriptome analyses, we observed that HOTAIR-EZH2-complex-regulated genes can efficiently discriminate between non-tumoral, recurrent, and non-recurrent bladder cancer samples. We also observed a significant correlation between EZH2 and HOTAIR expression levels. Using overexpression, knockdown, and pharmacological approaches in bladder cancer cell lines, we also observed that EZH2 regulates HOTAIR expression. Conclusions: Our findings indicate that HOTAIR expression has prognostic value for bladder cancer progression, recurrence, and survival and suggest that HOTAIR plays active roles in modulating the cancer epigenome, becoming an interesting candidate as a target for cancer diagnosis and therapy. The observed HOTAIR regulation by EZH2 and the possibility of modulating EZH2 activity with specific inhibitors open new possible paths to be explored in bladder cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
33. An Integrative Multi-scale Analysis of the Dynamic DNA Methylation Landscape in Aging.
- Author
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Yuan, Tian, Jiao, Yinming, de Jong, Simone, Ophoff, Roel A., Beck, Stephan, and Teschendorff, Andrew E.
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GENETICS of aging ,DNA methylation ,CELL differentiation ,EPIGENETICS ,GENETIC drift ,HUMAN genome ,GENE expression - Abstract
Recent studies have demonstrated that the DNA methylome changes with age. This epigenetic drift may have deep implications for cellular differentiation and disease development. However, it remains unclear how much of this drift is functional or caused by underlying changes in cell subtype composition. Moreover, no study has yet comprehensively explored epigenetic drift at different genomic length scales and in relation to regulatory elements. Here we conduct an in-depth analysis of epigenetic drift in blood tissue. We demonstrate that most of the age-associated drift is independent of the increase in the granulocyte to lymphocyte ratio that accompanies aging and that enrichment of age-hypermethylated CpG islands increases upon adjustment for cellular composition. We further find that drift has only a minimal impact on in-cis gene expression, acting primarily to stabilize pre-existing baseline expression levels. By studying epigenetic drift at different genomic length scales, we demonstrate the existence of mega-base scale age-associated hypomethylated blocks, covering approximately 14% of the human genome, and which exhibit preferential hypomethylation in age-matched cancer tissue. Importantly, we demonstrate the feasibility of integrating Illumina 450k DNA methylation with ENCODE data to identify transcription factors with key roles in cellular development and aging. Specifically, we identify REST and regulatory factors of the histone methyltransferase MLL complex, whose function may be disrupted in aging. In summary, most of the epigenetic drift seen in blood is independent of changes in blood cell type composition, and exhibits patterns at different genomic length scales reminiscent of those seen in cancer. Integration of Illumina 450k with appropriate ENCODE data may represent a fruitful approach to identify transcription factors with key roles in aging and disease. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
34. Probe Lasso: A novel method to rope in differentially methylated regions with 450K DNA methylation data.
- Author
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Butcher, Lee M. and Beck, Stephan
- Subjects
- *
DNA methylation , *METHYLCYTOSINE , *DNA methyltransferases , *DATA analysis , *METHYLATION - Abstract
The speed and resolution at which we can scour the genome for DNA methylation changes has improved immeasurably in the last 10 years and the advent of the Illumina 450K BeadChip has made epigenome-wide association studies (EWAS) a reality. The resulting datasets are conveniently formatted to allow easy alignment of significant hits to genes and genetic features, however; methods that parse significant hits into discreet differentially methylated regions (DMRs) remain a challenge to implement. In this paper we present details of a novel DMR caller, the Probe Lasso: a flexible window based approach that gathers neighbouring significant-signals to define clear DMR boundaries for subsequent in-depth analysis. The method is implemented in the R package ChAMP (Morris et al., 2014) and returns sets of DMRs according to user-tuned levels of probe filtering (e.g., inclusion of sex chromosomes, polymorphisms) and probe-lasso size distribution. Using a sub-sample of colon cancer- and healthy colon-samples from TCGA we show that Probe Lasso shifts DMR calling away from just probe-dense regions, and calls a range of DMR sizes ranging from tens-of-bases to tens-of-kilobases in scale. Moreover, using TCGA data we show that Probe Lasso leverages more information from the array and highlights a potential role of hypomethylated transcription factor binding motifs not discoverable using a basic, fixed-window approach. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
35. Analysis pipelines and packages for Infinium HumanMethylation450 BeadChip (450k) data.
- Author
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Morris, Tiffany J. and Beck, Stephan
- Subjects
- *
PIPELINE contractors , *HYDRAULIC structures , *DATA analysis , *DEOXYRIBOSE , *NUCLEIC acids - Abstract
The Illumina HumanMethylation450 BeadChip has become a popular platform for interrogating DNA methylation in epigenome-wide association studies (EWAS) and related projects as well as resource efforts such as the International Cancer Genome Consortium (ICGC) and the International Human Epigenome Consortium (IHEC). This has resulted in an exponential increase of 450k data in recent years and triggered the development of numerous integrated analysis pipelines and stand-alone packages. This review will introduce and discuss the currently most popular pipelines and packages and is particularly aimed at new 450k users. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
36. The Dynamics of DNA Methylation Covariation Patterns in Carcinogenesis.
- Author
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Teschendorff, Andrew E., Liu, Xiaoping, Caren, Helena, Pollard, Steve M., Beck, Stephan, Widschwendter, Martin, and Chen, Luonan
- Subjects
CARCINOGENESIS ,DNA methylation ,CANCER research ,CANCER invasiveness ,CANCER risk factors ,CERVICAL intraepithelial neoplasia ,PAPILLOMAVIRUS diseases - Abstract
Recently it has been observed that cancer tissue is characterised by an increased variability in DNA methylation patterns. However, how the correlative patterns in genome-wide DNA methylation change during the carcinogenic progress has not yet been explored. Here we study genome-wide inter-CpG correlations in DNA methylation, in addition to single site variability, during cervical carcinogenesis. We demonstrate how the study of changes in DNA methylation covariation patterns across normal, intra-epithelial neoplasia and invasive cancer allows the identification of CpG sites that indicate the risk of neoplastic transformation in stages prior to neoplasia. Importantly, we show that the covariation in DNA methylation at these risk CpG loci is maximal immediately prior to the onset of cancer, supporting the view that high epigenetic diversity in normal cells increases the risk of cancer. Consistent with this, we observe that invasive cancers exhibit increased covariation in DNA methylation at the risk CpG sites relative to normal tissue, but lower levels relative to pre-cancerous lesions. We further show that the identified risk CpG sites undergo preferential DNA methylation changes in relation to human papilloma virus infection and age. Results are validated in independent data including prospectively collected samples prior to neoplastic transformation. Our data are consistent with a phase transition model of carcinogenesis, in which epigenetic diversity is maximal prior to the onset of cancer. The model and algorithm proposed here may allow, in future, network biomarkers predicting the risk of neoplastic transformation to be identified. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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- View/download PDF
37. Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases.
- Author
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Wilson, Gareth A., Butcher, Lee M., Foster, Holly R., Feber, Andrew, Roos, Christian, Walter, Lutz, Woszczek, Grzegorz, Beck, Stephan, and Bell, Christopher G.
- Subjects
EPIGENETICS ,LEUKOTRIENES ,DISEASE susceptibility ,PATHOGENIC microorganisms ,DNA methylation ,IMMUNE system ,NEUTROPHILS - Abstract
Background Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment's influence on the epigenome, and therefore genome function, as well as conversely the genome's facilitative effect on the epigenome, analysis of this level of regulation may increase our knowledge of disease pathogenesis. Methods In order to identify human-specific epigenetic influences, we have performed a novel genome-wide DNA methylation analysis comparing human, chimpanzee and rhesus macaque. Results We have identified that the immunological Leukotriene B4 receptor (LTB4R, BLT1 receptor) is the most epigenetically divergent human gene in peripheral blood in comparison with other primates. This difference is due to the co-ordinated active state of human-specific hypomethylation in the promoter and human-specific increased gene body methylation. This gene is vital in innate immunity, and the LTB4/LTB4R pathway is involved in the pathogenesis of the spectrum of human inflammatory diseases. This finding was confirmed by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Additionally we show through functional analysis that this receptor has increased expression and a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. Genome-wide we also find human speciesspecific differentially methylated regions (human s-DMRs) are more prevalent in CpG island shores than within the islands themselves, and within the latter are associated with the CTCF motif. Conclusions This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from very closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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38. DNA methylation analysis of murine hematopoietic side population cells during aging.
- Author
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Taiwo, Oluwatosin, Wilson, Gareth A., Emmett, Warren, Morris, Tiffany, Bonnet, Dominique, Schuster, Eugene, Adejumo, Tomas, Beck, Stephan, and Pearce, Daniel J.
- Published
- 2013
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39. The Relationship between Epigenetic Age and Myocardial Infarction/Acute Coronary Syndrome in a Population-Based Nested Case-Control Study.
- Author
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Malyutina, Sofia, Chervova, Olga, Tillmann, Taavi, Maximov, Vladimir, Ryabikov, Andrew, Gafarov, Valery, Hubacek, Jaroslav A., Pikhart, Hynek, Beck, Stephan, and Bobak, Martin
- Subjects
ACUTE coronary syndrome ,MYOCARDIAL infarction ,CASE-control method ,AGE ,EPIGENETICS ,DNA methylation - Abstract
We investigated the relationship between 'epigenetic age' (EA) derived from DNA methylation (DNAm) and myocardial infarction (MI)/acute coronary syndrome (ACS). A random population sample was examined in 2003/2005 (n = 9360, 45–69, the HAPIEE project) and followed up for 15 years. From this cohort, incident MI/ACS (cases, n = 129) and age- and sex-stratified controls (n = 177) were selected for a nested case-control study. Baseline EA (Horvath's, Hannum's, PhenoAge, Skin and Blood) and the differences between EA and chronological age (CA) were calculated (ΔAHr, ΔAHn, ΔAPh, ΔASB). EAs by Horvath's, Hannum's and Skin and Blood were close to CA (median absolute difference, MAD, of 1.08, –1.91 and –2.03 years); PhenoAge had MAD of −9.29 years vs. CA. The adjusted odds ratios (ORs) of MI/ACS per 1–year increments of ΔAHr, ΔAHn, ΔASB and ΔAPh were 1.01 (95% CI 0.95–1.07), 1.01 (95% CI 0.95–1.08), 1.02 (95% CI 0.97–1.06) and 1.01 (0.93–1.09), respectively. When classified into tertiles, only the highest tertile of ΔAPh showed a suggestion of increased risk of MI/ACS with OR 2.09 (1.11–3.94) independent of age and 1.84 (0.99–3.52) in the age- and sex-adjusted model. Metabolic modulation may be the likely mechanism of this association. In conclusion, this case-control study nested in a prospective population-based cohort did not find strong associations between accelerated epigenetic age markers and risk of MI/ACS. Larger cohort studies are needed to re-examine this important research question. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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40. Human-specific CpG "beacons" identify loci associated with human-specific traits and disease.
- Author
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Bell, Christopher G., Wilson, Gareth A., Butcher, Lee M., Roos, Christian, Walter, Lutz, and Beck, Stephan
- Published
- 2012
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41. The epigenomic interface between genome and environment in common complex diseases.
- Author
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Bell, Christopher G. and Beck, Stephan
- Subjects
- *
MEDICAL genetics , *GENOMICS , *METHYLATION , *ETIOLOGY of diseases , *DNA - Abstract
The epigenome plays the pivotal role as interface between genome and environment. True genome-wide assessments of epigenetic marks, such as DNA methylation (methylomes) or chromatin modifications (chromatinomes), are now possible, either through high-throughput arrays or increasingly by second-generation DNA sequencing methods. The ability to collect these data at this level of resolution enables us to begin to be able to propose detailed questions, and interrogate this information, with regards to changes that occur due to development, lineage and tissue-specificity, and significantly those caused by environmental influence, such as ageing, stress, diet, hormones or toxins. Common complex traits are under variable levels of genetic influence and additionally epigenetic effect. The detection of pathological epigenetic alterations will reveal additional insights into their aetiology and how possible environmental modulation of this mechanism may occur. Due to the reversibility of these marks, the potential for sequence-specific targeted therapeutics exists. This review surveys recent epigenomic advances and their current and prospective application to the study of common diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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42. Global hypomethylation in myeloma is associated with poor prognosis.
- Author
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Sive, Jonathan I., Feber, Andrew, Smith, Dean, Quinn, John, Beck, Stephan, and Yong, Kwee
- Subjects
MULTIPLE myeloma ,METHYLATION ,GENETIC regulation ,PATIENTS ,PROGNOSIS - Abstract
The article focuses on study related to multiple myeloma and role of global hypomethylation in myeloma which is associated with poor prognosis. Topics discussed include methylation patterns which include global hypomethylation in asymptomatic myeloma and hypermethylation in symptomatic myeloma; role of transcription start site in regulation of gene expression; and relevance of gene promoter hypomethylation to survival outcomes in myeloma patients.
- Published
- 2016
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43. EpiDISH web server: Epigenetic Dissection of Intra-Sample-Heterogeneity with online GUI.
- Author
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Zheng, Shijie C, Breeze, Charles E, Beck, Stephan, Dong, Danyue, Zhu, Tianyu, Ma, Liangxiao, Ye, Wei, Zhang, Guoqing, and Teschendorff, Andrew E
- Subjects
INTERNET servers ,WEB-based user interfaces ,EPIGENETICS ,UPLOADING of data ,PLANT genetics ,DECONVOLUTION (Mathematics) - Abstract
Summary It is well recognized that cell-type heterogeneity hampers the interpretation of Epigenome-Wide Association Studies (EWAS). Many tools have emerged to address this issue, including several R/Bioconductor packages that infer cell-type composition. Here we present a web application for cell-type deconvolution, which offers the functionality of our EpiDISH Bioconductor/R package in a user-friendly GUI environment. Users can upload their data to infer cell-type composition and differentially methylated cytosines in individual cell-types for a range of different tissues. Availability and implementation EpiDISH web server is implemented with Shiny in R, and is freely available at https://www.biosino.org/EpiDISH/. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
44. Brave new epigenomes: the dawn of epigenetic engineering.
- Author
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KÕeferle, Anna, Stricker, Stefan H., and Beck, Stephan
- Subjects
EPIGENETICS ,GENOME editing ,GENOMES ,CHROMATIN ,ZINC-finger proteins ,DNA-binding proteins - Abstract
New methods for epigenome editing now make it possible to manipulate the epigenome in living cells with unprecedented specificity and efficiency. These ground-breaking approaches are beginning to yield novel insights into the function of individual chromatin marks in the context of cellular phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
45. Advances in epigenome-wide association studies for common diseases.
- Author
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Paul, Dirk S. and Beck, Stephan
- Subjects
- *
DISEASE research , *FUTURES studies , *BIOMARKERS , *EPIGENETICS , *DNA methylation - Abstract
Epigenome-wide association studies (EWASs) provide a systematic approach to uncovering epigenetic variants underlying common diseases. Discoveries have shed light on novel molecular mechanisms of disease and enabled the application of epigenetic variants as biomarkers. Here, we highlight the recent advances in this emerging line of research and discuss key challenges for current and future studies. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
46. BLUEPRINT to decode the epigenetic signature written in blood.
- Author
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Adams, David, Altucci, Lucia, Antonarakis, Stylianos E, Ballesteros, Juan, Beck, Stephan, Bird, Adrian, Bock, Christoph, Boehm, Bernhard, Campo, Elias, Caricasole, Andrea, Dahl, Fredrik, Dermitzakis, Emmanouil T, Enver, Tariq, Esteller, Manel, Estivill, Xavier, Ferguson-Smith, Anne, Fitzgibbon, Jude, Flicek, Paul, Giehl, Claudia, and Graf, Thomas
- Subjects
BLOOD cells ,PHENOTYPIC plasticity ,GENETIC code ,EPIGENETICS ,GENOTYPE-environment interaction - Abstract
The article discusses the European Union (EU)-funded consortium called BLUEPRINT that aims to generate epigenomic maps of at least 100 different blood cell types. The mapping of the blood cell types will be conducted by the International Human Epigenome Consortium (IHEC). Among the goals of BLUEPRINT are the systematic linking of epigenetic variation with phenotypic plasticity in health and disease and the comprehensive review of diverse epigenomic maps.
- Published
- 2012
- Full Text
- View/download PDF
47. Potential (mis)use of epigenetic age estimators by private companies and public agencies: human rights law should provide ethical guidance.
- Author
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Dupras, Charles, Beck, Stephan, Rothstein, Mark A, Berner, Alison, Saulnier, Katie M, Pinkesz, Miriam, Prince, Anya E R, Liosi, Stamatina, Song, Lingqiao, and Joly, Yann
- Subjects
HUMAN rights ,EPIGENETICS ,DNA methylation - Abstract
Over the past decade, researchers in epigenetics have developed testing methods to predict the chronological and biological age of individuals based on levels of DNA methylation at combinations of CpG sites in specific cell types. These epigenetic age and aging estimators, also referred to as 'epigenetic clocks', represent a promising avenue to better understand the biological pathways underlying the development of aging-associated disorders, and imagine biomedical and/or social interventions to prevent, reverse, or alleviate them. Epigenetic clock technologies aimed at testing for epigenetic age of different cell types also provide an opportunity to investigate how environmental stressors, social adversity, and unhealthy lifestyle can contribute to such disorders through epigenetic aging acceleration. In addition to their potential clinical and public health applications, epigenetic age and aging estimators may be used for non-medical purposes, such as insurance and forensic sciences. In this article, we present and discuss a set of potential ethical, legal, and social implications of non-medical uses of epigenetic clocks. We highlight concerns related to actuarial and moral fairness, free and informed consent, data governance and the protection of privacy, equity and non-discrimination principles, identification and surveillance, the moral liability of criminals, as well as scientific validity, test accuracy, and interpretation of test results. We argue that a human rights framework should guide further discussions about these important and timely questions. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
48. Epigenetic and Transcriptional Variability Shape Phenotypic Plasticity
- Author
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Ecker, Simone, Pancaldi, Vera, Valencia, Alfonso, Beck, Stephan, and Paul, Dirk S
- Subjects
genome architecture ,DNA methylation ,Biological Variation, Individual ,epigenetics ,Transcription, Genetic ,variability ,Genetic Variation ,biological noise ,Adaptation, Physiological ,Chromatin ,3. Good health ,Epigenesis, Genetic ,3D chromatin structure ,Biological Variation, Population ,gene expression ,Humans ,heterogeneity ,Precision Medicine ,transcription - Abstract
Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. In this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. We highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. Further, we provide an overview of challenges in the analysis of biological variability. An improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra- and inter-individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine.
49. Epigenetic Noise Fuels Cancer Evolution.
- Author
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Swanton, Charles and Beck, Stephan
- Subjects
- *
EPIGENETICS , *CANCER genetics , *GENOMES , *GENETIC mutation , *HUMAN genetic variation , *DNA methylation - Abstract
Cancer is a disease of the genome and the epigenome. Previous studies have shown that genomic changes such as mutations, copy number variation, and genomic rearrangements drive cancer evolution. In this issue of Cancer Cell , Landau and colleagues add epigenomic changes, specifically locally disordered DNA methylation, to cancer’s evolutionary trajectory. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
50. Erratum to: Brave new epigenomes: the dawn of epigenetic engineering.
- Author
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Köferle, Anna, Stricker, Stefan H., and Beck, Stephan
- Subjects
EPIGENETICS ,GENOMES - Abstract
A correction to the article "Brave new epigenomes: the dawn of epigenetic engineering," by Stefan Stricker and colleagues is presented.
- Published
- 2015
- Full Text
- View/download PDF
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