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Diagnosis and Pathobiology
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
All cells of the body generally contain the same genome. However, it is the information stored within the epigenetic code that regulates many aspects of the genome and reveals itself across various physiological, pathological, and developmental stages including cellular/tissue differentiation and lineage commitment [364–366]. Epigenetics, a term coined by Waddington in 1942, is the study of heritable changes in gene expression that occur independently of the basic DNA sequence and results in a phenotype modification without genotype modification [366, 367]. Since genetic material is not physically changed, epigenetic programming guarantees the inheritance of untouched genomic information from parents to offspring [296, 364] The epigenetic code is cell- and tissue-specific, and the literature identifies over 90,000 individual and over 400 different types of epigenetic modifications [368]. Epigenetics plays a seminal role in cancer. The ‘two-hit' model proposed by Knudson suggests cancer initiation follows from the interconnection of independent epimutations (a heritable change in DNA that does not involve an actual DNA mutation) that silence tumor-suppressor genes (the first hit) and deleterious genetic mutations or deletions (the second hit) that disrupt normal cellular processes [369]. Furthermore, in cancer progression, signals from the tumor microenvironment influence cancer epigenomes because stress induced by the tumor environment (e.g., inflammation, hypoxia) and/or by the therapeutic intervention may reshape the chromatin landscape, engendering epigenetic plasticity. This can promote intrinsic cellular reprogramming and cancer stemness, the molecular processes governing the fundamental stem cell properties of self-renewal and propagation of differentiated daughter cells [370, 371]) by way of a slow-cycling or semiquiescent phenotype persister state (where cells are resistant to a wide range of treatments and remain viable under conditions that kill surrounding cells [371]), as well as epithelial-mesenchymal plasticity (i.e., the ability to reversibly switch between a static adherent state and detached mobile state [372]), messenger RNA epitranscriptomic regulation (different RNA modifications such as covalent modifications like methylation that are added to individual nucleotides to regulate the stability, translation, and immunogenicity of RNA molecules [373]), and resistance to therapy [268, 272, 283, 371, 374–376]. Therefore, it is both the nucleotide sequence and these additional epigenetic modifications that regulate the function of the mRNAs transcribed from a given gene [373].
Early-life adversity-induced long-term epigenetic programming associated with early onset of chronic physical aggression: Studies in humans and animals
Published in The World Journal of Biological Psychiatry, 2019
Dimitry A. Chistiakov, Vladimir P. Chekhonin
A basic structural unit of chromatin is a nucleosome consisting of an octamer of core histones H2A, H2B, H3, H4 and a 147-bp long DNA that wraps around the histone core. Histone H1 serves as an internucleosomal link, which is implicated in the generation of higher hierarchical structures (Kornberg 1974). Each of the core histones contains the globular domain that contributes to the nucleosome core and N-terminal tail, which stands out towards the DNA. In this tail, histone residues are subjected to modifications such as methylation and acetylation, which can be added or removed by chromatin-remodelling enzymes (Wolffe & Hayes 1999). Histone modifications lead to chromatin structural/conformational changes and serve as recognition sites for specific factors such ATP-dependent remodelling enzymes, transcriptional complex, etc. Certain combinations of these modifications (i.e., specific epigenetic marks, or ‘epigenetic indexing code’) can be sensed by distinct proteins, which differentially recognise these combinations with help of DNA-binding domains (Strahl & Allis 2000). This epigenetic machinery reads the ‘epigenetic code’ and transduces epigenetic changes to gene expression (Borrelli et al. 2008). Indeed, the ‘epigenetic code’ induced by epigenetic programming (that arises from the influence of environmental factors such as childhood adversity, etc.) can mediate long-lasting effects of early-life experience on adulthood and be released by an appropriate epigenetic machinery (Sun et al. 2013).
Gordon H. Dixon’s trace in my personal career and the quantic jump experienced in regulatory information
Published in Systems Biology in Reproductive Medicine, 2018
It is not completely understood if H1 is able to read the nucleosome code or if it is an effector protein regulating the core Histone PTMs in a locus specific manner. Histone H1 is able to alter the epigenetic code and interface with particular modified core histone states (see review by Fyodorov et al. 2018). It is a well-known fact that H1 occupancy strongly correlates with hypoacetylation of core histones (Schröter et al. 1981; Reczek et al. 1982). H1 can repress histone acetylation by negatively regulating histone acetyltransferases (HATs) (Herrera et al. 2000). It is also required for the maintenance of female germ line stem cells in Drosophila melanogaster, where its depletion selectively increases H4K16 acetylation and cause premature differentiation (Sun et al. 2015).
Beyond EZH2: is the polycomb protein CBX2 an emerging target for anti-cancer therapy?
Published in Expert Opinion on Therapeutic Targets, 2019
Maïka Jangal, Benjamin Lebeau, Michael Witcher
Due to the importance of PTMs in dictating gene expression patterns and their dynamic mode of action, epigenetic marks are key mediators of homeostasis, rapid transcriptional responses to external signaling and cell differentiation. Further, epigenetic marks are invariably reprogrammed or erased in cancer, leading to the aberrant activation of oncogenes and repression of tumor suppressor genes. As such, targeting epigenetic enzymes, including readers and writers of the epigenetic code, has become an area of great interest in cancer research [3].