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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 Aug 2021Deciphering the principles and mechanisms by which gene activity orchestrates complex cellular arrangements in multicellular organisms has far-reaching implications for... (Review)
Review
Deciphering the principles and mechanisms by which gene activity orchestrates complex cellular arrangements in multicellular organisms has far-reaching implications for research in the life sciences. Recent technological advances in next-generation sequencing- and imaging-based approaches have established the power of spatial transcriptomics to measure expression levels of all or most genes systematically throughout tissue space, and have been adopted to generate biological insights in neuroscience, development and plant biology as well as to investigate a range of disease contexts, including cancer. Similar to datasets made possible by genomic sequencing and population health surveys, the large-scale atlases generated by this technology lend themselves to exploratory data analysis for hypothesis generation. Here we review spatial transcriptomic technologies and describe the repertoire of operations available for paths of analysis of the resulting data. Spatial transcriptomics can also be deployed for hypothesis testing using experimental designs that compare time points or conditions-including genetic or environmental perturbations. Finally, spatial transcriptomic data are naturally amenable to integration with other data modalities, providing an expandable framework for insight into tissue organization.
Topics: Animals; Data Analysis; Disease; Gene Expression Profiling; Humans; Organ Specificity; Transcription, Genetic; Transcriptome
PubMed: 34381231
DOI: 10.1038/s41586-021-03634-9 -
Annual Review of Pathology Jan 2020The dynamic properties of mitochondria-including their fusion, fission, and degradation-are critical for their optimal function in energy generation. The interplay of... (Review)
Review
The dynamic properties of mitochondria-including their fusion, fission, and degradation-are critical for their optimal function in energy generation. The interplay of fusion and fission confers widespread benefits on mitochondria, including efficient transport, increased homogenization of the mitochondrial population, and efficient oxidative phosphorylation. These benefits arise through control of morphology, content exchange, equitable inheritance of mitochondria, maintenance of high-quality mitochondrial DNA, and segregation of damaged mitochondria for degradation. The key components of the machinery mediating mitochondrial fusion and fission belong to the dynamin family of GTPases that utilize GTP hydrolysis to drive mechanical work on biological membranes. Defects in this machinery cause a range of diseases that especially affect the nervous system. In addition, several common diseases, including neurodegenerative diseases and cancer, strongly affect mitochondrial dynamics.
Topics: Animals; DNA, Mitochondrial; Disease; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Dynamics; Neurodegenerative Diseases
PubMed: 31585519
DOI: 10.1146/annurev-pathmechdis-012419-032711 -
Science (New York, N.Y.) Nov 2021Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic...
Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3892 plasma proteins to create a cis-anchored gene-protein-disease map of 1859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to connect etiologically related diseases, to provide biological context for new or emerging disorders, and to integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at loci identified in genome-wide association studies, thereby addressing a major barrier to experimental validation and clinical translation of genetic discoveries.
Topics: Aging; Alternative Splicing; Blood Proteins; COVID-19; Connective Tissue Diseases; Disease; Drug Development; Female; Gallstones; Genetic Association Studies; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomics; Humans; Internet; Male; Phenotype; Proteins; Proteome; Quantitative Trait Loci; Sex Characteristics
PubMed: 34648354
DOI: 10.1126/science.abj1541 -
Journal of Cellular Physiology Aug 2022The circadian system is responsible for internal functions and regulation of the organism according to environmental cues (zeitgebers). Circadian rhythm dysregulation or... (Review)
Review
The circadian system is responsible for internal functions and regulation of the organism according to environmental cues (zeitgebers). Circadian rhythm dysregulation or chronodisruption has been associated with several diseases, from mental to autoimmune diseases, and with life quality change. Following this, some therapies have been developed to correct circadian misalignments, such as light therapy and chronobiotics. In this manuscript, we describe the circadian-related diseases so far investigated, and studies reporting relevant data on this topic, evidencing this relationship, are included. Despite the actual limitations in published work, there is clear evidence of the correlation between circadian rhythm dysregulation and disease origin/development, and, in this way, clock-related therapies emerge as great progress in the clinical field. Future improvements in such interventions can lead to the development of successful chronotherapy strategies, deeply contributing to enhanced therapeutic outcomes.
Topics: Chronobiology Disorders; Circadian Rhythm; Disease; Humans
PubMed: 35696609
DOI: 10.1002/jcp.30815 -
Nature Genetics Dec 2021The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured...
The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development.
Topics: Biomarkers; Blood Proteins; Disease; Female; Gene Frequency; Genetic Variation; Genome-Wide Association Study; Humans; Male; Middle Aged; Proteome; Quantitative Trait Loci
PubMed: 34857953
DOI: 10.1038/s41588-021-00978-w -
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 -
Nature Reviews. Drug Discovery Jun 2021Antisense technology is now beginning to deliver on its promise to treat diseases by targeting RNA. Nine single-stranded antisense oligonucleotide (ASO) drugs... (Review)
Review
Antisense technology is now beginning to deliver on its promise to treat diseases by targeting RNA. Nine single-stranded antisense oligonucleotide (ASO) drugs representing four chemical classes, two mechanisms of action and four routes of administration have been approved for commercial use, including the first RNA-targeted drug to be a major commercial success, nusinersen. Although all the approved drugs are for use in patients with rare diseases, many of the ASOs in late- and middle-stage clinical development are intended to treat patients with very common diseases. ASOs in development are showing substantial improvements in potency and performance based on advances in medicinal chemistry, understanding of molecular mechanisms and targeted delivery. Moreover, the ASOs in development include additional mechanisms of action and routes of administration such as aerosol and oral formulations. Here, we describe the key technological advances that have enabled this progress and discuss recent clinical trials that illustrate the impact of these advances on the performance of ASOs in a wide range of therapeutic applications. We also consider strategic issues such as target selection and provide perspectives on the future of the field.
Topics: Animals; Biological Therapy; Chemistry, Pharmaceutical; Disease; Drug Delivery Systems; Humans; Oligonucleotides, Antisense
PubMed: 33762737
DOI: 10.1038/s41573-021-00162-z -
Seminars in Hematology Oct 2021
Topics: Hematologic Diseases; Humans; Syndrome
PubMed: 34802540
DOI: 10.1053/j.seminhematol.2021.10.005 -
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