1,721,020 research outputs found
Insights in human epigenomic dynamics through comparative primate analysis
No full textEpigenomic analysis gives a molecular insight into cell-specific genomic activity. It provides a detailed functional plan to dissect an organism, tissue by tissue. Therefore comparative epigenomics may increase understanding of human-acquired traits, by revealing regulatory changes in systems such as the neurological, musculoskeletal, and immunological.Enhancer loci evolve fast by hijacking elements from other tissues or rewiring and amplifying existing units for human-specific function. Promoters by contrast often require a CpG dense genetic infrastructure. Specific interplay occurs between the two, but also a shared modality of function, with coordination from global chromatin-modifying enzymes. Changes in specific transcription factor binding sites also facilitate the local epigenetic state. In the case of CTCF, these may further influence 3-dimensional structure and interaction.How these mechanistic units are modulated between tissue and species enables more comprehensive understanding of human processes and pathology. With this information, precise therapeutic targeting of these epigenetic modifications may become possible
Integration of genomic and epigenomic DNA methylation data in common complex diseases by haplotype-specific methylation analysis
No full textThe analysis of complex diseases was revolutionized by the ability to genotype at a genome-wide level tagging common SNPs in sufficiently large, and therefore adequately powered, population sample sets. This technological breakthrough has led to thousands of genetic variants being robustly associated with a multitude of phenotypic traits. These findings have illuminated novel genes and previously unknown pathways in the pathogenesis of disease, although in the majority of loci the functional mechanism remains unknown. The integration of this genomic information with epigenomic and transcriptomic data from these regions is one of the next steps in unraveling their biological significance. Allele-specific methylation influences allele-specific expression; therefore, the methylation state of the haplotypes within genetically associated regions can determine epigenetic differences with potential functional effects. DNA methylation data and association-determined risk and nonrisk haplotypes can be compared by a haplotype-specific methylation analysis. These are the first forays into what will become an increasingly routine multidimensional analysis as whole-genome, epigenome and transcriptome sequencing data become easily obtainable, with existing second- and soon to be available third-generation sequencing analyzers. Concise understanding of the functional implications of these genome-wide association-derived risk factors, plus rare variants discovered from deep sequencing experiments currently underway, will enable personalized risk and prevention profiling, as well as treatment, to come to fruition
The epigenomic analysis of human obesity
No full textThe epigenome - the chemical modifications and packaging of the genome that can influence or indicate its activity - gives a molecular insight to cell-type specific workings. It can, therefore, reveal the pathophysiological mechanisms at work in disease. Detected changes can also represent physiological responses to adverse environmental exposures, thus enabling the epigenetic mark of DNA methylation to act as an epidemiological biomarker, even in surrogate tissue.This makes epigenomic analysis an attractive prospect to further understand the pathobiology and epidemiological aspects of obesity. Furthermore, integrating epigenomic data with known obesity-associated common genetic variation can aid in deciphering their molecular mechanisms.This review primarily examines epidemiological or population-based studies of epigenetic modifications in relation to adiposity-traits, as opposed to animal or cell models. It discusses recent work exploring the epigenome with respect to human obesity, which to date have predominately been array-based studies of DNA methylation in peripheral blood. It is of note that highly replicated BMI DNA methylation associations are not causal, but strongly driven by co-associations for more precisely measured intertwined outcomes and factors, such as hyperlipidaemia, hyperglycaemia and inflammation. Finally, the potential for the future exploration of the epigenome in obesity and related disorders will be considered.<br/
Advances in the identification and analysis of allele-specific expression
Full text linkAllele-specific expression (ASE) is essential for normal development and many cellular processes but, if impaired, can result in disease. ASE is a feature of organisms with genomes consisting of more than one set of homologous chromosomes. The higher the number of chromosome sets (ploidy) per cell, the higher the potential complexity of ASE. Humans, for instance, are diploid (except germ cells, which are haploid), resulting in multiple possible expression states in time and space for each set of alleles. ASE is invoked and modulated by both genetic and epigenetic changes, affecting the underlying DNA sequence or chromatin of each allele, respectively. Although numerous methods have been developed to assay ASE, they usually require RNA to be available and are dependent upon genetic polymorphisms (such as single nucleotide polymorphisms (SNPs)) to differentiate between allelic transcripts. The rapid convergence to second-generation sequencing as the method of choice to examine genomic, epigenomic and transcriptomic data enables an integrated and more general approach to define and predict ASE, independent of SNPs. This 'Omni-Seq' approach has the potential to advance our understanding of the biology and pathophysiology of ASE-mediated processes by elucidating subtle combinatorial effects, leading to the accurate delineation of sub-phenotypes with consequential benefit for improved insight into disease etiology
The epigenomic interface between genome and environment in common complex diseases
No full textThe 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 disease
Epigenome-wide association studies: potential insights into human disease
No full textThe burden on human health due to common diseases, such as the metabolic syndrome, cardiovascular and inflammatory disorders is extreme. With increasingly longer lived populations, the morbidity of these chronic conditions leads to vast physical, psychological and economic cost. In order to further understand the pathogenicity of these complex diseases, the intertwined influence of environmental factors and polygenic susceptibility needs to be unravelled. This may at first seem an insurmountably difficult task but progress has been made in recent year
Using epigenomic studies in monozygotic twins to improve our understanding of cancer
Full text linkCancer is a set of diseases that exhibit not only genetic mutations but also a profoundly distorted epigenetic landscape. Over the last two decades, great advances have been made in identifying these alterations and their importance in the initiation and progression of cancer. Epigenetic changes can be seen from the very early stages in tumorigenesis and dysregulation of the epigenome has an increasingly acknowledged pathogenic role. Epigenomic twin studies have great potential to contribute to our understanding of complex diseases, such as cancer. This is because the use of monozygotic twins discordant for cancer enables epigenetic variation analysis without the confounding influence of the constitutive genetic background, age or cohort effects. It therefore allows the identification of susceptibility loci that may be sensitive to modification by the environment. These studies into cancer etiology will potentially lead to robust epigenetic markers for the detection and risk assessment of cance
Cancer detection and tissue of origin determination with novel annotation and scoring of cell-free methylated DNA
Full text linkIn a recent paper, Guo et al. (1) analysed the methylation of DNA fragments circulating in the blood plasma that are released when cells die. Their analysis used a novel approach to annotate DNA methylation and a methylation status score, which captures both average methylation level and the pattern of co-methylation. They were able to detect lung and colorectal cancers and to predict their tissue of origin
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