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The Parasite's Way of Life
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
As discussed in Chapter 2 (see Figure 2.34) histones are an especially important type of DNA-associated protein found in chromatin. The addition of methyl groups (methylation) to histone proteins is well-known as a mechanism that regulates whether associated DNA is in the heterochromatin or euchromatin form. Methyl groups are added to specific amino acid residues by a group of enzymes called methyltransferases. Histone methylation can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated and how many methyl groups are added. Methylation events that weaken chemical attractions between histones and DNA increase transcription because they enable the DNA to uncoil, allowing transcription factors and RNA polymerase to access the DNA.
Exercise, Metabolism and Oxidative Stress in the Epigenetic Landscape
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Gareth W. Davison, Colum P. Walsh
Methylation of histone H3 and H4 is via histone methyltransferase (HMT) enzymes that covalently add CH3 from SAM onto the side-chain nitrogen atoms of mainly lysine and arginine residues (Vanzan et al., 2017; Wong et al., 2017). Lysine methyltransferases contain a conserved domain Su(var)3–9, Enhancer of zeste and Trithorax (SET) responsible for adding CH3 specifically at H3K4, H3K9, H3K27 and H3K36 (Vanzan et al., 2017). The consequence of histone methylation is determined by the specific histone residue modified, the number of methyl groups added (mono-, di- or tri-methylation), and the location within the N-terminal regions of either H3 or H4 (Kaelin and McKnight, 2013; Etchegaray and Mostoslavsky, 2016). These changes lead to a state of either euchromatin (lightly packed DNA promoting transcription) or heterochromatin (condensed DNA suppressing transcription; Figure 17.1) (Davison et al., 2021).
Genetics and genomics of exposure to high altitude
Published in Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson, Ward, Milledge and West's High Altitude Medicine and Physiology, 2021
Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson
In addition to examining genetic and genomic contributions to phenotypes, various other large-scale “-omic” approaches are employed to characterize global patterns of gene expression (e.g., transcriptomics) as well as protein and metabolic profiles (proteomics and metabolomics, respectively) in both tissue- and development-specific contexts. Epigenetic modifications, alterations in gene expression above (“epi”) the DNA nucleotide sequence, change in response to environmental cues and are therefore highly relevant in the context of the high altitude environment. Specific markers on the histone proteins that package DNA or direct methylation of specific DNA nucleotides result in heterochromatin and euchromatin states, which preclude and promote transcription of DNA, respectively. Methylome and genome-wide DNA hypersensitivity assays are additional -omics approaches that provide complementary insights into genome-wide patterns of cellular and molecular function.
Epigenetic control of skin immunity
Published in Immunological Medicine, 2023
Human cells contain two meters of genomic DNA that is tightly folded and packed within the nucleus. Genomic DNA forms a secondary structure referred to as chromatin that fits into a limited space [7]. The basic unit of chromatin, the nucleosome, is consisted of 147 bp genomic DNA and a core histone octamer. DNA is negatively charged and histones are positively charged, and the opposing charges allow DNA to wrap itself tightly around the histone octamer to form a nucleosome. Initiation of transcription requires the binding of RNA polymerase II and several basic transcription factors, called TFIIA and TFIIB, bind to promoters located near the transcription start sites [8]. Sequence-specific DNA-binding transcription factors (TFs) are involved in the enhancement of transcription. TFs bind to enhancers and cause genomic DNA to form looped structures that shorten the distance between enhancers and promoters, thereby promoting the transcription of the target genes. Transcriptional activity is also closely related to the degree of DNA condensation associated with chromatin structure [6,8]. Tightly packed chromatin, called closed chromatin or heterochromatin, restricts the access of RNA polymerase II and the transcription factors to the regulatory sites, and consequently, suppresses the expression of target genes. Open chromatin or euchromatin that is less condensed allows easier access of the transcriptional machinery to DNA, thus setting target genes to be more actively transcribed.
Chaetocin induced chromatin condensation: effect on DNA repair signaling and survival
Published in International Journal of Radiation Biology, 2021
A. Sak, K. Bannik, M. Groneberg, M. Stuschke
Chaetocin was reported to be a potential inhibitor of SUV39h1 which tri-methylates histone H3 at K9 (H3K9me3). Thus, we explore the effect of chaetocin on methylation of H3K9 as a measure for SUV39h1 activity. For this purpose, cells were treated for 48 h with chaetocin, histone proteins were isolated and the level of the histone variants was studied by immunoblotting assay. At concentrations of ≤300 nM, corresponding to about 10x IC50 for proliferation, there was no effect of chaetocin on global trimethylation of H3K9 (Figure 5). To explore directly the effect of the HKMT SUV39h1 on the global methylation pattern of H3K9, cells were treated with shRNA and expression of SUV39h1 protein was determined (Figure 6). Treatment with SUV39h1 shRNA significantly downregulated its expression to about 50% of the non-treated cells and thereby reduced global di- and tri-methylation of H3K9, both used as a measure for heterochromatin. On the other hand, the fraction of mono-methylated H3K9 as a measure for euchromatin, increased significantly after downregulating SUV39h1 expression. These data showed that H3K9 di- and tri-methylation can be used as a measure for SUV39h1 activity.
Promising novel therapies for relapsed and refractory testicular germ cell tumors
Published in Expert Review of Anticancer Therapy, 2021
Kristyna Kozakova, Michal Mego, Liang Cheng, Michal Chovanec
Histone acetylation serves as a switching point between euchromatin activation and deactivation (see in Figure 3). It is mainly coordinated by HDAC, which can be divided into four classes. Accumulation of hyperacetylated histones leads to upregulation of stress markers in TGCT cells what eventually leads to growth arrest and apoptosis. That is why histone deacetylation inhibitors may serve as another promising additive drug to overcome resistance to cisplatin [149,150]. HDAC1 from the first classified group showed the highest expression of all HDACs in testicular GCTs. Moreover, given the fact, that HDAC1 levels do not significantly differ between the GCT histological subgroups, it was chosen as the primary target for the GCT treatment [150]. In preclinical studies, there has been confirmed that treatment of cisplatin-resistant GCT cell lines with HDAC inhibitor romidepsin efficiently deters the cell cycle and induces apoptosis even at the very low dosage and does not affect viability of Sertoli cells or fibroblasts [150–152]. Other study uncovered a strong synergic effect of romidepsin in a combination with glucocorticoid dexamethasone [153], what might open another possibilities for treatment of GCT.