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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
RNA Interference (RNAi) is a natural process that occurs in all cells and is thought to have evolved as a protection mechanism against RNA viruses. It may also play a role in RNAi-related pathways such as shaping the chromatin structure of a genome. The cell responds to the introduction of extraneous dsRNA by destroying all intracellular mRNA of the same sequence. The phenomenon was first observed in the Caenorhabditis elegans worm and later in drosophila, trypanosomes, and planaria. The post-transcriptional gene silencing (PTGS) observed in plants is thought to operate through a similar RNAi mechanism.
The Role of Epigenetics in Skeletal Muscle Adaptations to Exercise and Exercise Training
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Both DNA methylation and histone modifications influence gene expression by altering chromatin structure and architecture. Chromatin is composed of repeating units of DNA wrapped around a core of histone proteins, which also form the larger chromosomes that tightly pack our genetic material into the nucleus (21). The extent of chromatin folding and the spatial relationship between DNA and histones have profound effects on transcription. Active gene transcription is generally associated with open chromatin, where DNA regions are assessable to transcriptional machinery such as the transcriptional initiation complex and RNA polymerase (21). Inactive gene regions are mostly associated with a closed chromatin structure, where transcriptional regulators cannot access gene regions (21). In contrast to these chromatin-focused mechanisms, non-coding RNA influences gene expression by regulating messenger RNA (mRNA) stability and translation.
The Opioid Epidemic
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Morphine also impacts epigenetic mechanisms that result in hyperalgesia and tolerance by changes in long-term gene expression in the pain system. Histone acetylation and deacetylation help to control gene expression. Histone acetyltransferase (HAT) enzymes transfer an acetyl group onto histones. The result is a more relaxed chromatin structure (euchromatin) and greater gene transcription. This relaxed structure can be “undone” by histone deacetylase (HDAC) transforming to a more condensed form (heterochromatin). Increasing morphine dose enhances the expression of acetylated histone H3 lysine9 (aceH3K9) in the dorsal spinal cord, which regulates the expression of dynorphin and brain-derived neurotrophic factor (BDNF).21 HAT inhibitors prior to morphine exposure (such as curcumin) have reduced the development of opioid-induced hyperalgesia.1,22 Conversely, HDAC inhibitor injections after morphine exposure prolong the morphine hyperalgesia and tolerance.22 Preventing the acetylation of histones or blocking BDNF or dynorphin may reduce hyperalgesia.
Inhibition of EZH2 mitigates peritoneal fibrosis and lipid precipitation in peritoneal mesothelial cells mediated by klotho
Published in Renal Failure, 2023
Qinglian Wang, Jingshu Sun, Rong Wang, Jing Sun
Enhancer of zeste homolog 2 (EZH2) is a histone lysine methyltransferase that catalyzes the methylation of histones. Histone modification leads to altered chromatin structure and affects the accessibility of transcription factor DNA promoters. Currently, research on EZH2 is mainly focused on its role in tumorigenesis, and inhibition of EZH2 activity has become a new strategy for antitumor therapy. In addition, studies also revealed that EZH2 had a close relationship with hepatic fibrosis, kidney fibrosis and bone marrow fibrosis. In our previous research, we found that GSK343 (an inhibitor of EZH2) exhibited protective effects in high glucose-treated human peritoneal mesothelial cells (HPMCs) [7]. However, whether it plays a role by reducing lipid deposition is still unclear. In the present study, we further explored the related mechanism in peritoneal fibrosis.
A look into the use of Raman spectroscopy for brain and breast cancer diagnostics: linear and non-linear optics in cancer research as a gateway to tumor cell identity
Published in Expert Review of Molecular Diagnostics, 2020
Halina Abramczyk, Beata Brozek-Pluska, Arkadiusz Jarota, Jakub Surmacki, Anna Imiela, Monika Kopec
Briefly, DNA/histone epigenetic modifications can be explained as follows. Genomic DNA is tightly packaged in chromatin by both histone and nonhistone proteins in the nucleus of eukaryotic cells. The basic chromatin subunits, nucleosomes, are formed by wrapping 146 base pairs (bp) of DNA around an octamer of four core histones: H2A, H2B, H3, and H4. Whereas the nucleosomal core is compact, eight flexible lysine-rich histone tails protrude from the nucleosome that modulates internucleosomal contacts and provides binding sites for nonhistone proteins. From the perspective of gene transcription, chromatin structure can be divided into two distinct categories: euchromatin and heterochromatin. ‘Euchromatin’ is an open chromatin structure that affords accessibility of transcription factors to DNA, resulting in gene activation. In contrast, ‘heterochromatin’ is a closed chromatin structure with a low interaction between transcription factors and the genome, leading to gene repression [94,95].
Indirect regulation of CYP2C19 gene expression via DNA methylation
Published in Xenobiotica, 2018
Kathryn Elisa Burns, Phillip Shepherd, Graeme Finlay, Malcolm Drummond Tingle, Nuala Ann Helsby
Differences in the expression of genes may occur at the transcriptional and/or translational level, and can be regulated via epigenetic mechanisms. Alterations in chromatin structure and/or the secondary structure of DNA may change chromatin accessibility and therefore gene expression. For example, the acetylation status of histones is regulated by histone acetyltransferase and deacetylase enzymes. Deacetylated histones are associated with a closed chromatin structure that prevents the transcriptional machinery accessing genomic DNA and results in gene “silencing”. In addition, mammalian DNA methyltransferase (DNMT) enzymes can methylate cytosine (C) nucleobases in the DNA molecule. Regions of the genome enriched in CpG dinucleotides, known as CpG islands, can become hyper-methylated. When this occurs at CpG islands close to the promoter region or transcription start site (TSS) of a gene the initiation of transcription is blocked, resulting in gene silencing.