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Epigenetics Dec 2019Growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis of cancer. Unlike genetic mutations, the ability to... (Review)
Review
Growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis of cancer. Unlike genetic mutations, the ability to reprogram the epigenetic landscape in the cancer epigenome is one of the most promising target therapies in both treatment and reversibility of drug resistance. Epigenetic alterations in cancer development and progression may be the basis for the individual variation in drug response. Thus, this review focuses on the emerging area of pharmaco(epi)genomics, specifically highlighting epigenetic reprogramming during tumorigenesis and how epigenetic markers are targeted as a therapy (epidrugs) and the clinical implications of this for cancer treatment.
Topics: Animals; Antineoplastic Agents; Epigenesis, Genetic; Epigenomics; Humans; Neoplasms; Pharmacogenetics
PubMed: 31282279
DOI: 10.1080/15592294.2019.1640546 -
PLoS Genetics Jun 2018Defects in chromatin modifiers and remodelers have been described both for hematological and solid malignancies, corroborating and strengthening the role of epigenetic... (Review)
Review
Defects in chromatin modifiers and remodelers have been described both for hematological and solid malignancies, corroborating and strengthening the role of epigenetic aberrations in the etiology of cancer. Furthermore, epigenetic marks-DNA methylation, histone modifications, chromatin remodeling, and microRNA-can be considered potential markers of cancer development and progression. Here, we review whether altered epigenetic landscapes are merely a consequence of chromatin modifier/remodeler aberrations or a hallmark of cancer etiology. We critically evaluate current knowledge on causal epigenetic aberrations and examine to what extent the prioritization of (epi)genetic deregulations can be assessed in cancer as some type of genetic lesion characterizing solid cancer progression. We also discuss the multiple challenges in developing compounds targeting epigenetic enzymes (named epidrugs) for epigenetic-based therapies. The implementation of acquired knowledge of epigenetic biomarkers for patient stratification, together with the development of next-generation epidrugs and predictive models, will take our understanding and use of cancer epigenetics in diagnosis, prognosis, and treatment of cancer patients to a new level.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Chromatin Assembly and Disassembly; DNA Methylation; Disease Progression; Enzyme Inhibitors; Enzymes; Epigenesis, Genetic; Epigenomics; Gene Expression Regulation, Neoplastic; Histone Code; Humans; MicroRNAs; Molecular Targeted Therapy; Neoplasms; Prognosis
PubMed: 29879107
DOI: 10.1371/journal.pgen.1007362 -
Circulation Research Apr 2021Calcific aortic valve disease sits at the confluence of multiple world-wide epidemics of aging, obesity, diabetes, and renal dysfunction, and its prevalence is expected... (Review)
Review
Calcific aortic valve disease sits at the confluence of multiple world-wide epidemics of aging, obesity, diabetes, and renal dysfunction, and its prevalence is expected to nearly triple over the next 3 decades. This is of particularly dire clinical relevance, as calcific aortic valve disease can progress rapidly to aortic stenosis, heart failure, and eventually premature death. Unlike in atherosclerosis, and despite the heavy clinical toll, to date, no pharmacotherapy has proven effective to halt calcific aortic valve disease progression, with invasive and costly aortic valve replacement representing the only treatment option currently available. This substantial gap in care is largely because of our still-limited understanding of both normal aortic valve biology and the key regulatory mechanisms that drive disease initiation and progression. Drug discovery is further hampered by the inherent intricacy of the valvular microenvironment: a unique anatomic structure, a complex mixture of dynamic biomechanical forces, and diverse and multipotent cell populations collectively contributing to this currently intractable problem. One promising and rapidly evolving tactic is the application of multiomics approaches to fully define disease pathogenesis. Herein, we summarize the application of (epi)genomics, transcriptomics, proteomics, and metabolomics to the study of valvular heart disease. We also discuss recent forays toward the omics-based characterization of valvular (patho)biology at single-cell resolution; these efforts promise to shed new light on cellular heterogeneity in healthy and diseased valvular tissues and represent the potential to efficaciously target and treat key cell subpopulations. Last, we discuss systems biology- and network medicine-based strategies to extract meaning, mechanisms, and prioritized drug targets from multiomics datasets.
Topics: Aortic Valve; Aortic Valve Stenosis; Biomechanical Phenomena; Calcinosis; Computational Biology; Disease Progression; Drug Discovery; Epigenesis, Genetic; Gene Expression; Genomics; Heart Failure; Humans; Mass Spectrometry; Medical Illustration; Metabolomics; Phenotype; Proteomics; Transcatheter Aortic Valve Replacement; Transcriptome
PubMed: 33914608
DOI: 10.1161/CIRCRESAHA.120.317979 -
Gerontology 2018Forensic genetics developed from protein-based techniques a quarter of a century ago and became famous as "DNA fingerprinting," this being based on restriction fragment... (Review)
Review
Forensic genetics developed from protein-based techniques a quarter of a century ago and became famous as "DNA fingerprinting," this being based on restriction fragment length polymorphisms (RFLPs) of high-molecular-weight DNA. The amplification of much smaller short tandem repeat (STR) sequences using the polymerase chain reaction soon replaced RFLP analysis and advanced to become the gold standard in genetic identification. Meanwhile, STR multiplexes have been developed and made commercially available which simultaneously amplify up to 30 STR loci from as little as 15 cells or fewer. The enormous information content that comes with the large variety of observed STR genotypes allows for genetic individualisation (with the exception of identical twins). Carefully selected core STR loci form the basis of intelligence-led DNA databases that provide investigative leads by linking unsolved crime scenes and criminals through their matched STR profiles. Nevertheless, the success of modern DNA fingerprinting depends on the availability of reference material from suspects. In order to provide new investigative leads in cases where such reference samples are absent, forensic scientists started to explore the prediction of phenotypic traits from the DNA of the evidentiary sample. This paradigm change now uses DNA and epigenetic markers to forecast characteristics that are useful to triage further investigative work. So far, the best investigated externally visible characteristics are eye, hair and skin colour, as well as geographic ancestry and age. Information on the chronological age of a stain donor (or any sample donor) is elemental for forensic investigations in a number of aspects and has, therefore, been explored by researchers in some detail. Among different methodological approaches tested to date, the methylation-sensitive analysis of carefully selected DNA markers (CpG sites) has brought the most promising results by providing prediction accuracies of ±3-4 years, which can be comparable to, or even surpass those from, eyewitness reports. This mini-review puts recent developments in age estimation via (epi)genetic methods in the context of the requirements and goals of forensic genetics and highlights paths to follow in the future of forensic genomics.
Topics: Aging; CpG Islands; DNA Fingerprinting; Databases, Nucleic Acid; Epigenomics; Forensic Genetics; Humans; Microsatellite Repeats
PubMed: 29393215
DOI: 10.1159/000486239 -
Nature Reviews. Cancer Jun 2014Infection of cervical epithelium with high-risk human papilloma virus (hrHPV) might result in productive or transforming cervical intraepithelial neoplasia (CIN)... (Review)
Review
Infection of cervical epithelium with high-risk human papilloma virus (hrHPV) might result in productive or transforming cervical intraepithelial neoplasia (CIN) lesions, the morphology of which can overlap. In transforming CIN lesions, aberrations in host cell genes accumulate over time, which is necessary for the ultimate progression to cancer. On the basis of (epi)genetic changes, early and advanced transforming CIN lesions can be distinguished. This paves the way for new molecular tools for cervical screening, diagnosis and management of cervical cancer precursor lesions.
Topics: Biomarkers, Tumor; Cell Transformation, Neoplastic; Epigenomics; Female; Humans; Papillomaviridae; Papillomavirus Infections; Precancerous Conditions; Uterine Cervical Neoplasms; Uterine Cervical Dysplasia
PubMed: 24854082
DOI: 10.1038/nrc3728 -
Frontiers in Genetics 2022
PubMed: 35865017
DOI: 10.3389/fgene.2022.961232 -
Frontiers in Cardiovascular Medicine 2022Unveiling the secrets of genome's flexibility does not only foster new research in the field, but also gives rise to the exploration and development of novel... (Review)
Review
Unveiling the secrets of genome's flexibility does not only foster new research in the field, but also gives rise to the exploration and development of novel epigenetic-based therapies as an approach to alleviate disease phenotypes. A better understanding of chromatin biology (DNA/histone complexes) and non-coding RNAs (ncRNAs) has enabled the development of epigenetic drugs able to modulate transcriptional programs implicated in cardiovascular diseases. This particularly applies to heart failure, where epigenetic networks have shown to underpin several pathological features, such as left ventricular hypertrophy, fibrosis, cardiomyocyte apoptosis and microvascular dysfunction. Targeting epigenetic signals might represent a promising approach, especially in patients with heart failure with preserved ejection fraction (HFpEF), where prognosis remains poor and breakthrough therapies have yet to be approved. In this setting, epigenetics can be employed for the development of customized therapeutic approaches thus paving the way for personalized medicine. Even though the beneficial effects of epi-drugs are gaining attention, the number of epigenetic compounds used in the clinical practice remains low suggesting that more selective epi-drugs are needed. From DNA-methylation changes to non-coding RNAs, we can establish brand-new regulations for drug targets with the aim of restoring healthy epigenomes and transcriptional programs in the failing heart. In the present review, we bring the timeline of epi-drug discovery and development, thus highlighting the emerging role of epigenetic therapies in heart failure.
PubMed: 35911511
DOI: 10.3389/fcvm.2022.923014 -
Redox Biology Jun 2023Nutrigenomics describes the interaction between nutrients and our genome. Since the origin of our species most of these nutrient-gene communication pathways have not... (Review)
Review
Nutrigenomics describes the interaction between nutrients and our genome. Since the origin of our species most of these nutrient-gene communication pathways have not changed. However, our genome experienced over the past 50,000 years a number of evolutionary pressures, which are based on the migration to new environments concerning geography and climate, the transition from hunter-gatherers to farmers including the zoonotic transfer of many pathogenic microbes and the rather recent change of societies to a preferentially sedentary lifestyle and the dominance of Western diet. Human populations responded to these challenges not only by specific anthropometric adaptations, such as skin color and body stature, but also through diversity in dietary intake and different resistance to complex diseases like the metabolic syndrome, cancer and immune disorders. The genetic basis of this adaptation process has been investigated by whole genome genotyping and sequencing including that of DNA extracted from ancient bones. In addition to genomic changes, also the programming of epigenomes in pre- and postnatal phases of life has an important contribution to the response to environmental changes. Thus, insight into the variation of our (epi)genome in the context of our individual's risk for developing complex diseases, helps to understand the evolutionary basis how and why we become ill. This review will discuss the relation of diet, modern environment and our (epi)genome including aspects of redox biology. This has numerous implications for the interpretation of the risks for disease and their prevention.
Topics: Humans; Nutrigenomics; Diet; Adaptation, Physiological
PubMed: 36933390
DOI: 10.1016/j.redox.2023.102656 -
Future Oncology (London, England) Jun 2017
Topics: Antigens, Nuclear; Antigens, Protozoan; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18; DNA Copy Number Variations; Epigenomics; Germ-Line Mutation; Humans; Oncogene Proteins, Fusion; RNA-Binding Protein EWS; Sarcoma, Ewing
PubMed: 28589731
DOI: 10.2217/fon-2017-0159 -
Communications Biology Feb 2021Single-cell multi-omics are powerful means to study cell-to-cell heterogeneity. Here, we present a single-tube, bisulfite-free method for the simultaneous, genome-wide...
Single-cell multi-omics are powerful means to study cell-to-cell heterogeneity. Here, we present a single-tube, bisulfite-free method for the simultaneous, genome-wide analysis of DNA methylation and genetic variants in single cells: epigenomics and genomics of single cells analyzed by restriction (epi-gSCAR). By applying this method, we obtained DNA methylation measurements of up to 506,063 CpGs and up to 1,244,188 single-nucleotide variants from single acute myeloid leukemia-derived cells. We demonstrate that epi-gSCAR generates accurate and reproducible measurements of DNA methylation and allows to differentiate between cell lines based on the DNA methylation and genetic profiles.
Topics: Cell Line, Tumor; CpG Islands; DNA Methylation; Epigenesis, Genetic; Epigenome; Epigenomics; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid, Acute; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; RNA-Seq; Reproducibility of Results; Single-Cell Analysis
PubMed: 33526904
DOI: 10.1038/s42003-021-01661-w