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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Another mechanism involves a physical change in the location of nucleosomes. These noncovalent mechanisms play a significant role in chromatin structure and gene regulation. Nucleosomes not only help to pack the DNA within the nucleus of cells but also enable transcription factors to access the regulatory regions of DNA sequences to facilitate gene expression. At the 5’- and 3’-ends of genes there are nucleosome-free-regions (NFRs) (Figure 11.16) which are thought to be responsible for transcription factor assembly and disassembly. Having an NFR region at gene-promoter sites allows for rapid gene activation when stimulated. Conversely, if an NFR within a transcription start site is occluded, then this can lead to gene repression.
Atypical Teratoid / Rhabdoid Tumors – AT/RT
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Michael C. Frühwald, Jaclyn A. Biegel, Susan N. Chi
At the core of rhabdoid tumor pathogenesis lie mutations of epigenetic regulators, i.e., the core protein of the chromatin-remodeling complex SWI/SNF, SMARCB1. Chromatin, the nucleoprotein material of a chromosome, plays an important role in gene expression and is modified through movement, dissociation, or reconstitution. The basic unit of chromatin is made of 146 basepairs of DNA wrapped around an octamer of histone proteins which in their assembly are termed the nucleosome.23 Changes of the nucleosome are mediated by the action of different multiprotein chromatin remodelers. SWI/SNF is a major player in altering chromatin structure by ATP-dependent disruption of histone–DNA interactions and unpacking dense, complex, tertiary structures. The SWI/SNF complex plays an important role in the regulation of critical cellular processes such as cell cycle progression, programmed cell death, differentiation, gene transcription, and DNA repair.24–26
The Role of Epigenetics in Breast Cancer: Implications for Diagnosis, Prognosis, and Treatment
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Amy M. Dworkin, Tim H.-M. Huang, Amanda E. Toland
Along with methylation, posttranslational modification of histones plays an important role in epigenetics. Histone proteins associate with DNA to form nucleosomes, permitting large amounts of DNA to be neatly packaged into the nucleus. There are two configurations of chromatin, heterochromatin and euchromatin. Heterochromatin is condensed and transcriptionally inactive, while euchromatin has an “open” configuration and is favorable for gene transcription (Fig.2). The N-terminal tails of histones “stick out” of the nucleosome and are subject to posttranslational modification such as acetylation, phosphorylation, methylation, ubiquitination, and sumoylation (2,4,7,15). The pattern of histone modification creates a “code,” which is read by proteins involved in chromatin remodeling and the dynamics of gene transcription (6,11). Acetylation and deacteylation are the most common types of histone modification. Histone deacetylases (HDACs) are a class of enzymes that remove acetyl groups from a ε-N-acetyl lysine amino acid on a histone. Its action is opposite to that of histone acetyltransferases (HATs). Deacetylation removes acetyl groups from histone tails, causing the histones to wrap more tightly around the DNA and interfering with transcription by blocking access to transcription factors. The overall result of histone deacetylation is a global (nonspecific) reduction in gene expression (Table 1).
Maintaining a ‘fit’ immune system: the role of vaccines
Published in Expert Review of Vaccines, 2023
Béatrice Laupèze, T. Mark Doherty
Modification of histones is an important mechanism underlying ‘trained immunity’ [24]. Histones are structural proteins that wrap DNA into a condensed form (nucleosomes) in the nucleus. Modifications to the histone tail by acetylation of lysine or methylation of lysine or arginine have opposing actions on the architecture of the surrounding chromatin, making it easier or harder for the protein complexes involved in transcription to access gene promoter regions, respectively, thus leading to increased or decreased transcription [23]. Acetylation (generally linked to increased transcription) and methylation (generally linked to decreased transcription), at the extremes can promote a state of hyper-inflammation or immune tolerance, respectively [23,25]. Long-term changes to myeloid cell populations can be brought about by epigenetic, transcriptomic, and functional reprogramming of myeloid stem cells in the bone marrow.
Do small RNAs have potential in disease diagnosis and treatment?
Published in Expert Review of Molecular Diagnostics, 2021
Sushila Maan, Kanisht Batra, Narender Singh Maan
Several classes of small RNAs have emerged recently. Numerous aspects of their origins, structures, related effector proteins, and biological roles have led to the identification of three main categories: short interfering (si)RNAs, micro (mi)RNAs, and piwi-interacting (pi)RNAs. These small RNAs are regulated by two recently discovered miRNA-regulatory RNAs, namely competing endogenous (ce)RNA and circular (circ)RNA. Recently, another class of small RNAs (17–18 nt in length) was discovered in animals using deep sequencing approaches and these are found to be associated with transcription initiation (‘tiRNAs’) and splice sites (‘spliRNAs’). Initial studies suggest that they may play a role in nucleosome positioning and/or be involved in chromatin organization. There are also other reports of less distinct classes of promoter-associated RNAs called PASRs, TSSa-RNAs, and PROMPTS, some of which may play a role in RNA-directed transcriptional gene silencing.
In vitro cytotoxicity of polyphenols from Datura innoxia aqueous leaf-extract on human leukemia K562 cells: DNA and nuclear proteins as targets
Published in Drug and Chemical Toxicology, 2020
Elham Chamani, Roshanak Ebrahimi, Khatereh Khorsandi, Azadeh Meshkini, Asghar Zarban, Gholamreza Sharifzadeh
Studies have shown that DNA is a pharmacological target of many of the drugs currently in clinical use or in advanced clinical trials (Hurley and Boyd 1988, Sirajuddin et al. 2013). In the eukaryotes, nuclear DNA interacts with histone proteins and forms a nucleoprotein complex known as chromatin. Chromatin arranges the nuclear genome into a restricted volume. The first level of chromatin organization consists of DNA-folding around histone proteins to shape the fundamental unit of the chromatin, the nucleosome (Hübner et al. 2013). In a nucleosome, 147 bp of DNA are enfolded in an octamer with two copies of four core histone proteins (H2A, H2B, H3, and H4) (Nair and Kumar 2012). As a linker histone, histone H1 surrounds the chromatosome by protecting the internucleosomal linker DNA near the nucleosome entry-exit point (Dixon et al. 2016, Kalashnikova et al. 2016).