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Molecular adaptations to endurance exercise and skeletal muscle fibre plasticity
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Within the nucleus, our genome is condensed through tightly wrapping the long stranded DNA around histones. This tertiary structure of DNA needs to be remodelled (opened) before any gene can be expressed. The opening and closing of DNA is termed chromatin remodelling or epigenetic regulation and it has been shown that such regulation is key for myogenesis and probably also plays an important role in the regulation of MyHC isoform expression and fibre-type specification. Support for the important role of chromatin remodelling driving myogenesis comes from early experiments where fibroblasts were treated with 5-azacytidine, a drug that opens up DNA. Within days, the fibroblasts had turned into myoblasts because regions of the genome where muscle genes are located had become more accessible (53). Chromatin remodelling is tightly regulated by DNA methylation and by histone acetylation and methylation on lysine residues as described by the ‘histone code’ hypothesis (54).
DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jesus Duque, Michael Lübbert, Mark Kirschbaum
Epigenetic changes such as DNA methylation need to be maintained and transmitted to daughter cells, necessitating tight coordination among the various enzymes charged with histone regulation (1), for this reason a brief review of other histone related modifications is necessary to fully explicate the role of DNA methylation changes. Over 60 types of histone modification are described at this time, with a paradigm shift from the study of individual changes to that of signaling based on interrelationships between modification, which is referred to as the “histone code” (50). This implies that the modifications are read in terms of the overall set of changes at the histone tail, beyond the effect of any single modification alone, and at the organization level of nucleosomes.
Current developments in human stem cell research and clinical translation
Published in Christine Hauskeller, Arne Manzeschke, Anja Pichl, The Matrix of Stem Cell Research, 2019
Stephanie Sontag, Martin Zenke
In the stabilization phase, cells have already re-acquired pluripotency and this is maintained independently of exogenous reprogramming factors. It is reported that this stabilization phase continues for several passages after initial colony emergence (Chin et al., 2009). During this time, telomeres are elongated (Marion et al., 2009), (in female cells) the X-chromosome is re-activated (Stadtfeld et al., 2008), and the epigenetic memory is reset (Kim et al., 2011). The latter refers to epigenetic marks that remain from the somatic cell (hence somatic memory) and can result in differentiation propensities towards the previous somatic lineage. Note that, while in the initiation and the maturation phase, epigenetic information is remodelled by modifications in the histone code, and in the stabilization phase re-activated DNA methyltransferases erase somatic DNA methylation signatures (David and Polo, 2014). This process can be accelerated when iPSCs are cultured with DNA methyltransferase inhibitors, e.g. 5-azacytidine.
Advances in Hodgkin’s lymphoma pharmacotherapy: a focus on histone deacetylase inhibitors
Published in Expert Opinion on Pharmacotherapy, 2023
Thuy Ho, Cara Coleman, Palak Shah, Victor Yazbeck
Carcinogenesis is not only driven by genetic mutations but also by post-transcriptional modifications, which are heritable and therefore propagate through clonal cell lines [16]. Epigenetic regulation changes the expression of genes without altering the DNA sequence by various chemical processes, such as methylation, acetylation, phosphorylation, ubiquitylation, and sumoylation, at the level of histones [17]. Histones are protein octamers around which DNA is wrapped, forming nucleosomes that combine to produce chromatin [18]. Histone tails protrude from the nucleosome and undergo the aforementioned chemical modifications, creating a histone code, which alters the chromatin structure and subsequently many cellular functions. Histone acetylation is a reversible process, mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs catalyze the removal of acetyl groups from specific arginine and lysine residues on histone tails. Acetylated chromatin has a relaxed structure that is favorable for gene expression by enabling binding of transcription factors, whereas deacetylated chromatin has a closed structure, which supports transcription repression. Altered activity of HATs and HDACs leads to an imbalance of chromatin modifications and resultant expression of oncogenes. HDACs also play a role in regulating the acetylation of other key survival, non-histone proteins, which affect mRNA splicing, translation, and stability, as well as protein–protein interactions. Among the proteins that HDACs have been shown to modulate are p53, NFKB, and tubulin [18,19].
Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview
Published in Expert Opinion on Therapeutic Targets, 2019
Tyler S. McCann, Lays M. Sobral, Chelsea Self, Joseph Hsieh, Marybeth Sechler, Paul Jedlicka
Epigenetic mechanisms, long known to play key roles in development, have more recently emerged as playing diverse and important roles in the initiation and progression of cancer. In classical genetic terms, an epigenetic mechanism refers to a change in cellular phenotype that is not due to an alteration in DNA sequence, or genetic material. On a mechanistic level, epigenetic changes entail stable alterations in genomic output, or gene expression, due to changes in the chemical composition or/and structural conformation of chromatin. Chromatin, the structural and functional unit of the cellular genome, consists of repeating units of DNA wound around an octameric complex of histones, which together comprise the nucleosome. The DNA and protein components of chromatin each undergo dynamic chemical modifications. These include methylation and demethylation of DNA, and a variety of post-translational modifications involving specific residues in unstructured ‘tails’ of the core histones. Such modifications collectively constitute the ‘histone code’, which helps control the expression states of associated genes.
The relationship between histone posttranslational modification and DNA damage signaling and repair
Published in International Journal of Radiation Biology, 2019
Ajit K Sharma, Michael J. Hendzel
DNA damage and the DDR occur within a chromatin context (Agarwal and Miller 2016). The basic unit of chromatin is the nucleosome, which consists of ∼146 bp of nuclear DNA that is wrapped around the histone octamer containing two copies each of the core histones, H2A, H2B, H3 and H4 (Kornberg 1974). Chromatin structure and function is regulated by post-translational modifications (PTMs) of histones (Campos and Reinberg 2009; Suganuma and Workman 2011). During DNA damage sensing, repair, and recovery, histones undergo posttranslational modifications (PTMs) including phosphorylation, acetylation, methylation and ubiquitylation (Lukas et al. 2011; Miller and Jackson 2012). Such histone modifications could constitute a histone code for the DDR and direct the alteration of chromatin organization. A histone code for the DDR also marks the DNA damage site, facilitating recruitment of proteins involved in DNA damage sensing and repair processes (Lukas et al. 2011; Miller and Jackson 2012; Gong and Miller 2013; Jackson and Durocher 2013; Gong et al. 2016; Schwertman et al. 2016). Thus, the overall chromatin biochemistry regulates the DNA damage response. The DNA DSB response is also facilitated by hierarchical signaling networks that orchestrate chromatin structural changes that may coordinate cell-cycle checkpoints together with multiple enzymatic activities to repair broken DNA ends. In this review, we will summarize histone modifications that occur during the DDR and DSB repair processes.