Evolutionary Theories of Aging: A Systemic and Mechanistic Perspective
Shamim I. Ahmad in Aging: Exploring a Complex Phenomenon, 2017
Epigenetic modifications are dynamical adaptations of the structure of the chromatin which contribute to the regulation of gene transcription. The structure of the chromatin can be modified at the level of the histones, the predominant protein components of chromatin, via different molecular processes [43–46]. It has been demonstrated that the histone modifications are regulated by conserved protein modules and follow a well-organized dynamical scheme known as the histone code [47,48]. The apparent complexity of these dynamical structures is progressively better understood with the establishment of relationships between their topology and their dynamical behavior [49]. For example, the complexity of the regulatory machinery can be characterized in terms of generic properties such as robustness [50], modularity, and evolvability [51–53]. Within this framework, it is intuitively easier to understand how components of the proteome or genome participate together in many different processes which occur in different cellular compartments. As a consequence, a dysfunction of a small set of molecules affecting a restricted number of defined epigenetic [54] and metabolic processes [55,56] may propagate to all parts of the cell, leading to a progressive disruption of the general homeostasis. Hence, the systemic description of the organism naturally leads to the definition of aging as a dynamical and systemic process whose external symptoms are the disparate damages and ARDs described above [57,58].
DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
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.
Epigenetic Reprogramming in Early Embryo Development
Cristina Camprubí, Joan Blanco in Epigenetics and Assisted Reproduction, 2018
Histones are proteins that associate with DNA to package chromatin into nucleosomes which allows DNA condensation but also restricts access of regulatory factors to the DNA strand, affecting transcription. Histone tails are exposed on the nucleosome surface and they can be modified by addition of different molecules (acetylation, methylation, but also ubiquitination, SUMOylation, and phosphorylation) which alters the chromatin structure and increase or reduce its accessibility, according with the specific residue and/or the number of molecules that are added to histone amino acids. Histone tails modifications can correlate with different biological effects including DNA repression or activation, and configure a complex marking system called “histone code” (80,81). For example, histone acetylation affects chromatin structure (by decreasing interaction between positive charges on the histones and the negatively charged DNA) and facilitates the access of transcription factors to DNA. However, according with position and the number of methyl groups that are added to histone tails, it can correlate with either silencing (H3K9me3 and H3K27me3) or with activation (H3K4me3, H3K36me3) of DNA. But also histones modifications are connected to DNA methylation machinery or even protection of DNA from demethylation (82).
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.
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].
Related Knowledge Centers
- DNA
- DNA Methylation
- Epigenetic Code
- Histone
- Methylation
- Protein Domain
- Chromatin
- Nucleosome
- Chromosome
- N-Terminus