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Advances in Experimental Medicine and... 2020Epigenetic mechanisms, which include DNA methylation, histone modification, and microRNA (miRNA), can produce heritable phenotypic changes without a change in DNA... (Review)
Review
Epigenetic mechanisms, which include DNA methylation, histone modification, and microRNA (miRNA), can produce heritable phenotypic changes without a change in DNA sequence. Disruption of gene expression patterns which are governed by epigenetics can result in autoimmune diseases, cancers, and various other maladies. Mechanisms of epigenetics include DNA methylation (and demethylation), histone modifications, and non-coding RNAs such as microRNAs. Compared to numerous studies that have focused on the field of genetics, research on epigenetics is fairly recent. In contrast to genetic changes, which are difficult to reverse, epigenetic aberrations can be pharmaceutically reversible. The emerging tools of epigenetics can be used as preventive, diagnostic, and therapeutic markers. With the development of drugs that target the specific epigenetic mechanisms involved in the regulation of gene expression, development and utilization of epigenetic tools are an appropriate and effective approach that can be clinically applied to the treatment of various diseases.
Topics: Animals; DNA Methylation; Disease; Epigenesis, Genetic; Epigenomics; Health; Histone Code; Humans; MicroRNAs
PubMed: 32445090
DOI: 10.1007/978-981-15-3449-2_1 -
Nature Medicine Apr 2018Our understanding of the link between the human microbiome and disease, including obesity, inflammatory bowel disease, arthritis and autism, is rapidly expanding.... (Review)
Review
Our understanding of the link between the human microbiome and disease, including obesity, inflammatory bowel disease, arthritis and autism, is rapidly expanding. Improvements in the throughput and accuracy of DNA sequencing of the genomes of microbial communities that are associated with human samples, complemented by analysis of transcriptomes, proteomes, metabolomes and immunomes and by mechanistic experiments in model systems, have vastly improved our ability to understand the structure and function of the microbiome in both diseased and healthy states. However, many challenges remain. In this review, we focus on studies in humans to describe these challenges and propose strategies that leverage existing knowledge to move rapidly from correlation to causation and ultimately to translation into therapies.
Topics: Biomarkers; Disease; Humans; Life Style; Microbiota; Precision Medicine; Translational Research, Biomedical
PubMed: 29634682
DOI: 10.1038/nm.4517 -
Science (New York, N.Y.) Jan 2020Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the... (Review)
Review
Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.
Topics: Dietary Supplements; Disease; Exposome; Genome, Human; Health; Humans; Organic Chemicals; Physical Phenomena; Risk Assessment; Stress, Psychological
PubMed: 31974245
DOI: 10.1126/science.aay3164 -
Cell Jun 2017A central goal of genetics is to understand the links between genetic variation and disease. Intuitively, one might expect disease-causing variants to cluster into key... (Review)
Review
A central goal of genetics is to understand the links between genetic variation and disease. Intuitively, one might expect disease-causing variants to cluster into key pathways that drive disease etiology. But for complex traits, association signals tend to be spread across most of the genome-including near many genes without an obvious connection to disease. We propose that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and that most heritability can be explained by effects on genes outside core pathways. We refer to this hypothesis as an "omnigenic" model.
Topics: Animals; Disease; Genetic Diseases, Inborn; Genome-Wide Association Study; Genomics; Humans; Multifactorial Inheritance; Polymorphism, Single Nucleotide
PubMed: 28622505
DOI: 10.1016/j.cell.2017.05.038 -
The American Journal of Pathology Feb 2020Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway... (Review)
Review
Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. This form of regulated necrosis is represented by necroptosis, in which the receptor-interacting protein kinase-3 and its substrate mixed-lineage kinase domain-like protein play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell death has been found to occur in virtually all tissues and diseases evaluated. There are different immunologic consequences depending on whether cells die through apoptosis or necroptosis. Therefore, distinguishing between these two forms of cell death may be crucial during pathologic evaluations. In this review, we provide an understanding of necroptotic cell-death and highlight diseases in which necroptosis has been found to play a role. We also discuss the inhibitors of necroptosis and the ways these inhibitors have been used in preclinical models of diseases. These two discussions offer an understanding of the role of necroptosis in diseases and will foster efforts to pharmacologically target this unique yet pervasive form of programed cell death in the clinic.
Topics: Animals; Chronic Disease; Disease; Humans; Inflammation; Necroptosis
PubMed: 31783008
DOI: 10.1016/j.ajpath.2019.10.012 -
The EMBO Journal Mar 2021Various forms of cell death have been identified over the last decades with each relying on a different subset of proteins for the activation and execution of their... (Review)
Review
Various forms of cell death have been identified over the last decades with each relying on a different subset of proteins for the activation and execution of their respective pathway(s). In addition to the three best characterized pathways-apoptosis, necroptosis, and pyroptosis-other forms of regulated cell death including autophagy-dependent cell death (ADCD), mitochondrial permeability transition pore (MPTP)-mediated necrosis, parthanatos, NETosis and ferroptosis, and their relevance for organismal homeostasis are becoming better understood. Importantly, it is increasingly clear that none of these pathways operate alone. Instead, a more complex picture is emerging with many pathways sharing components and signaling principles. Finally, a number of cell death regulators are implicated in human diseases and represent attractive therapeutic targets. Therefore, better understanding of physiological and mechanistic aspects of cell death signaling should yield improved reagents for addressing unmet medical needs.
Topics: Cell Death; Disease; Humans; Signal Transduction
PubMed: 33439509
DOI: 10.15252/embj.2020106700 -
Annual Review of Pathology Jan 2020Organoids are in vitro-cultured three-dimensional structures that recapitulate key aspects of in vivo organs. They can be established from pluripotent stem cells and... (Review)
Review
Organoids are in vitro-cultured three-dimensional structures that recapitulate key aspects of in vivo organs. They can be established from pluripotent stem cells and from adult stem cells, the latter being the subject of this review. Organoids derived from adult stem cells exploit the tissue regeneration process that is driven by these cells, and they can be established directly from the healthy or diseased epithelium of many organs. Organoids are amenable to any experimental approach that has been developed for cell lines. Applications in experimental biology involve the modeling of tissue physiology and disease, including malignant, hereditary, and infectious diseases. Biobanks of patient-derived tumor organoids are used in drug development research, and they hold promise for developing personalized and regenerative medicine. In this review, we discuss the applications of adult stem cell-derived organoids in the laboratory and the clinic.
Topics: Adult; Adult Stem Cells; Cell Biology; Cell- and Tissue-Based Therapy; Disease; Humans; Organoids; Pluripotent Stem Cells; Regenerative Medicine
PubMed: 31550983
DOI: 10.1146/annurev-pathmechdis-012419-032611 -
Science (New York, N.Y.) Oct 2022Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic... (Review)
Review
Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic cellular barcodes, paired with single-cell readouts of cell state, have markedly increased our knowledge of clonal dynamics and genealogies of the cells that compose a variety of tissues and organs. These advances hold promise to redefine our view of human disease. Here, we provide an overview of cellular barcoding approaches, discuss applications to gain new insights into disease mechanisms, and provide an outlook on future applications. We discuss unanticipated insights gained through barcoding in studies of cancer and blood cell production and describe how barcoding can be applied to a growing array of medical fields, particularly with the increasing recognition of clonal contributions in human diseases.
Topics: Humans; DNA Barcoding, Taxonomic; Clonal Evolution; Disease; Single-Cell Analysis
PubMed: 36227997
DOI: 10.1126/science.abm5874 -
RNA (New York, N.Y.) Dec 2017RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has... (Review)
Review
RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.
Topics: Animals; Disease; Humans; RNA; RNA Processing, Post-Transcriptional
PubMed: 28855326
DOI: 10.1261/rna.063503.117 -
Science (New York, N.Y.) Feb 2015According to the disease module hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of...
According to the disease module hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of disease-associated genes, it is not obvious if the available data have sufficient coverage to map out modules associated with each disease. Here we derive mathematical conditions for the identifiability of disease modules and show that the network-based location of each disease module determines its pathobiological relationship to other diseases. For example, diseases with overlapping network modules show significant coexpression patterns, symptom similarity, and comorbidity, whereas diseases residing in separated network neighborhoods are phenotypically distinct. These tools represent an interactome-based platform to predict molecular commonalities between phenotypically related diseases, even if they do not share primary disease genes.
Topics: Comorbidity; Disease; Genetic Predisposition to Disease; Humans; Information Services; Protein Interaction Maps
PubMed: 25700523
DOI: 10.1126/science.1257601