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Mother and Embryo Cross Communication during Conception
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Anna Idelevich, Andrea Peralta, Felipe Vilella
Histone modification is another epigenetic mechanism. Histones are basic proteins acting as spools around which DNA winds, packaging it into structural units, called nucleosomes. A histone octamer consisting of two copies of each of the four core histones (H2A, H2B, H3, and H4), around which approximately 146 bp of the DNA winds, comprises a nucleosome. It has been shown that histones are subject to numerous covalent modifications, including methylation, acetylation, phosphorylation, sumoylation, glycosylation, and ubiquitination, at specific tails of selected amino acids. A number of enzymes are involved in this process, including histone methyltransferases (HMTs), acetyltransferases (HATs), kinases, and ubiquitin ligases functioning as writers, as well as erasers, such as histone demethylases, deacetylases (HDACs), and phosphatases, capable of removing modification marks from the histone tails. These modifications impose either transcriptionally repressive or transcriptionally permissive chromatin structures. For instance, histone acetylation usually results in active genes as does the di- or trimethylation of lysine residue 4 in histone H3 (H3K4me2, H3K4me3), whereas H3K9me2/3 and H3K27me3 modifications repress gene expression. In general, unlike DNA methylation, which is believed to confer a more stable and long-term silencing mechanism, various histone modifications seem to exert short-term, flexible regulation important for the plasticity of development [140–144].
The Emerging Role of Histone Deacetylase Inhibitors in the Treatment of Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Histones are the major structural proteins around which more than 2 m of DNA in every eukaryotic cell is organized. These proteins are considered to be small molecular weight proteins composed of a very high proportion of positively charged amino acids like lysine and arginine. This complex of histone protein, nonhistone protein, and DNA is often referred to as chromatin, the fundamental unit of which is referred to as the nucleosome. The nucleosome consists of a complex of approximately 150 bp of DNA and a histone octamer. Each histone octamer is comprised of a pair of histones including H2A, H2B, H3, and H4 (Fig. 1). Neighboring nucleosomes are linked together by DNA bound to the linker histone (H1). This complex assembly of protein and DNA provides an important organizational structure that helps the cell maintain control over transcription.
Stochastic multi-scale modeling of biological effects induced by ionizing radiation
Published in Issam El Naqa, A Guide to Outcome Modeling in Radiotherapy and Oncology, 2018
Werner Friedland, Pavel Kundrat
The target structures of DNA and chromatin in PARTRAC start with an atomic model representation of the DNA double-helix (Figure 10.11) and of a histone molecule based on X-ray crystallography data [433]. A DNA segment wrapped around a histone octamer serves as a model of the nucleosome, the most elementary repeating motif in chromatin. The next level of chromatin organization, the 30 nm fiber, is obtained by positioning one nucleosome after the other into a corresponding virtual tube and by connecting them with a linker DNA helix. The arrangement of subsequent nucleosomes determines the overall chromatin fiber structure. This is still a debated issue: Chromatin structures seem not to be uniform and regular, but have to be viewed in the context of specific biological functions [434]. The two-start zigzag topology and the type of linker DNA bending that defines solenoid models may be simultaneously present in a chromatin fiber with a uniform 30 nm diameter [435]. The DNA model in PARTRAC has the capability to describe regular or stochastic arrangements of nucleosomes in solenoidal as well as zigzag or crossed-linker topology [436]. In order to cope with the amount of DNA of about 6 Gbp (6 × 109 base pairs) in a human diploid cell, short pieces of a 30-nm chromatin fiber are used as building blocks for the entire genome. Five types of basic fiber elements are defined within cubic voxels of 40 or 50 nm edge length in which the chromatin fibre connects the bottom plane with one of the other five walls of the cube. For a seamless connection of these building blocks, the interface structure has to be identical. The interface may be reduced to a single nucleosome positioned between two boxes (see Figure 10.12); this allows consideration of two basic sets of building blocks with different compaction so as to describe hetero- and euchromatic structures [271]. When several nucleosomes are cut at the interface [290], the chromatin fiber may become very compact, with the underlying building block structure hardly discernible. The building blocks are generated by a special trial-and-error algorithm using the Monte Carlo technique: under given boundary conditions of fiber structure parameters and the already positioned nucleosomes, an additional nucleosome is placed, the linker DNA determined, and all the newly positioned atoms are tested for spatial overlap with the formerly arranged ones. In order to setup the building blocks for a highly compact chromatin fiber (with about 6 nucleosomes per 10 nm fiber length), the above trial-and-error procedure has to be executed several million times.
The current status of blood epigenetic biomarkers for dementia
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Peter D. Fransquet, Joanne Ryan
To date, histone modifications detected in blood as a possible biomarker of dementia has been less frequently investigated, but as a consequence, this field has much potential for growth and possibly exciting new findings. Histones have long been known to be responsible for the organisation of chromatin into nucleosomes. There are five protein families of histones, which include H1, the linker histone family, and four core histones, H2A, H2B, H3 and H4 [167]. These four histones compose the complex nucleosome structure, where DNA is wrapped around a histone octamer, comprised of a heterotetramer of H3 and H4, and surrounded by two heterodimers of H2A and H2B [168]. Histone modification includes covalent addition to the histone protein, usually at the amino-terminal and carboxy-terminal histone tail domains [168]. These modifications primarily include methylation, acetylation, phosphorylation and ubiquitination, but include several others, such as glycosylation, SUMOylation, 4-hydroxynonenalation [169,170]. Depending on what modification is added or removed, and where modifications are made on the histone, it is thought that modifications influence processes such as transcription, replication, recombination and DNA repair [171].
Emerging DNA methylation inhibitors for cancer therapy: challenges and prospects
Published in Expert Review of Precision Medicine and Drug Development, 2019
Aurora Gonzalez-Fierro, Alfonso Dueñas-González
The human genome is organized into 23 chromosomes so that each diploid cell with 46 chromosomes contains approximately 6 billion base pairs of DNA. If this DNA would be in a linearized form, each cell would have around 2-m length of DNA. Such amount of DNA must be packaged into the nucleus; hence, histone proteins mainly are responsible for organizing the long fibers of DNA within the nucleus. Both, the DNA complexed with histones are the elements of chromatin and the nucleosome is considered the functional unit of the genome. Nucleosomes are formed by a histone octamer formed by dimers of H2A, H2B, H3, and H4 which are linked by histone H1. Approximately 147 bp of superhelical DNA is wrapped around the histone octamer forming the nucleosome core particle [3]. Epigenetics, therefore, can be referred to as the study of all the elements involved in the regulation of nucleosome. Functionally, these elements are highly interacting in order to respond to the cells’ needs for proper regulation of gene expression in a time and cell-specific manner.
Epigenetic regulatory modifications in genetic and sporadic frontotemporal dementia
Published in Expert Review of Neurotherapeutics, 2018
Chiara Fenoglio, Elio Scarpini, Daniela Galimberti
In mammalian cells, histone proteins interact with DNA to form chromatin, the packaged form of DNA. Histones are octamers consisting of two copies of each of the four histone proteins: H2A, H2B, H3, and H4. Each histone octamer has 146 bps of the DNA stand wound around it to make up one nucleosome, which is the basic unit of chromatin. Histone proteins can be modified by post-translational changes. Among those there are acetylation, methylation, phosphorylation, ubiquitination, and citrullination. These histone modifications induce changes to the structure of chromatin and thereby affect the accessibility of the DNA strand to transcriptional enzymes, resulting in activation or repression of genes associated with the modified histone [25]. The best-understood histone modification is acetylation, which is mediated by histone acetyltransferases and deacetylases. Acetylation of histones is usually associated with upregulated transcriptional activity of the associated gene, whereas deacetylation of histones to transcriptional silencing [26].