Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The other important epigenetic mechanism is histone acetylation/deacetylation. The attraction of methyl-binding domain (MBD) proteins associated with histone deacetylases (HDACs) represents a more generalized effect, as the chromatin structure can be completely changed by these enzymes, profoundly affecting the expression of more than one gene. This process, known as chromatin remodeling, involves acetylation of the chromatin causing it to “open” and become more accessible to the necessary transcription factors, thus promoting gene expression. Conversely, gene silencing results from deacetylation of the histones, which causes the condensation of chromatin due to the positively charged lysine amino groups released interacting with the negatively charged DNA (Figure 5.108).
A Short Introduction to DNA Methylation
Cristina Camprubí, Joan Blanco in Epigenetics and Assisted Reproduction, 2018
Transcription does not occur on naked DNA but in the context of chromatin, which critically influences the accessibility of the DNA to transcription factors and the DNA polymerase complexes. DNA methylation, histone modifications and chromatin remodeling are closely linked and constitute multiple layers of epigenetic modifications to control and modulate gene expression through chromatin structure. DNMTs and histone deacetylases (HDACs) are found in the same multi-protein complexes and methyl CpG-binding domain proteins (MBDs) interact with HDACs, histone methyltransferases as well as with the chromatin remodeling complexes. Furthermore, mutations or loss of members of the SNF2 helicase/ATPase family of chromatin remodeling proteins such as ATRX or LSH lead to genome-wide perturbations of DNA methylation patterns and inappropriate gene expression programs.
Signal transduction and exercise
Adam P. Sharples, James P. Morton, Henning Wackerhage in Molecular Exercise Physiology, 2022
The full details of the transcription of a gene and the regulation of this process are beyond the scope of this chapter and are covered in detail in Chapter 3, but briefly here, important aspects of the control of transcription include: the unwinding of the tightly packed DNA, which is termed chromatin remodelling, which makes genes accessible;the recruitment of RNA polymerase II to the start of a gene;the rate at which RNA polymerase II transcribes the DNA of the gene into RNA andthe termination of transcription and recycling of RNA polymerase II.
Epigenetic changes involved in hydroquinone-induced mutations
Published in Toxin Reviews, 2021
Minjuan Zeng, Shaopeng Chen, Ke Zhang, Hairong Liang, Jie Bao, Yuting Chen, Shiheng Zhu, Wei Jiang, Hui Yang, Yixian Wei, Lihao Guo, Huanwen Tang
Chromatin remodeling is the dynamic modification of chromatin architecture and plays an important role in DNA repair and gene transcriptional regulation (Moore et al.2019). PARP-1, as a sensor of DNA damage, can regulate chromatin structure by interacting with ATP-dependent nucleosome remodeling enzymes, histones, and MeCP2 (Kraus and Hottiger 2013, Becker et al.2016). Compared to control cells, protein levels of PARP-1was upregulated in a dose-dependent manner in TK6 cells exposed 48 h to HQ (10, 20, and 40 μmol/L; Luo et al.2018). However, the expression of PARP-1 decreased to the lowest level within 3 h and then gradually increased in TK6 cells (treated with 10.0 μmol/L HQ for 1, 2, 3, 4, 5, and 6 h; Ling et al.2016). Caruso et al. (2018) showed that PARP-1 and PARylation are important regulators of EZH2 function and lead to decreased EZH2-mediated heterochromatin formation, increasing the reading and transcription of genes. Gui et al. (2019) reported that PARP-1 promotes expression of the tumor activator, miR-155, via upregulation of MBD2, a member of the same family as MeCP2, in TK6 cells exposed to HQ. Luo et al. (2018) speculated that overexpression of the tumor suppressor miR-7-5p suppresses cell proliferation and promotes apoptosis by inhibiting the DNA damage repair mediated via PARP-1 and BRCA1 in TK6 cells exposed to HQ.
High RSF1 protein expression is an independent prognostic feature in prostate cancer
Published in Acta Oncologica, 2020
Doris Höflmayer, Moslim Hamuda, Cornelia Schroeder, Claudia Hube-Magg, Ronald Simon, Cosima Göbel, Andrea Hinsch, Sören Weidemann, Katharina Möller, Jacob R. Izbicki, Frank Jacobsen, Tim Mandelkow, Niclas C. Blessin, Florian Lutz, Florian Viehweger, Guido Sauter, Eike Burandt, Patrick Lebok, Maximilian Lennartz, Christoph Fraune, Sarah Minner, Sarah Bonk, Hartwig Huland, Markus Graefen, Thorsten Schlomm, Franziska Büscheck
Remodelling and spacing factor 1 (RSF1) alias hepatitis B virus X protein associated protein is of potential clinical interest [4]. RSF1 is involved in the regulation of chromatin remodelling. It is a ubiquitously expressed histone chaperone, that interacts with specific chromatin remodelling factors [5]. Chromatin-remodelling complexes play a key role in all processes that require a change of the chromatin structure including DNA repair, DNA synthesis, and mitosis. RSF1 was reported to become overexpressed in various cancers including ovarian [6], lung [7], hepatocellular [8] or colon cancer [9]. Studies in ovarian [6], lung [7], nasopharyngeal [10], gastric [11], rectal [12] and urinary bladder cancer [13] suggested that its overexpression might be linked to poor patient prognosis. RSF1 overexpression was also found to potentially contribute to paclitaxel resistance [14], and cancers recurring after chemotherapy or radiotherapy showed higher RSF1 values than their respective primary tumours [15]. A role of RSF1 in modulating drug sensitivity was also supported by experiments showing that RSF1 knockdown by siRNA treatment reduced cell growth, increased drug sensitivity, and induced cell death in cancer cells with RSF1 overexpression [14,16].
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).
Related Knowledge Centers
- Acetylation
- Histone
- Histone Acetyltransferase
- Histone Deacetylase
- Methylation
- Ubiquitin
- Phosphorylation
- Chromatin
- Transcription
- Nucleosome