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Epigenetics of exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Daniel C. Turner, Robert A. Seaborne, Adam P. Sharples
As outlined above, histone modifications are regarded as one of the hallmark epigenetic regulators of the mammalian organism and a crucial dictator of cellular transcriptomic behaviour. Despite this, there is little work examining how RE training reprogrammes histone marks and what consequential affect this has on gene expression.
Epigenetics in Sperm, Epigenetic Diagnostics, and Transgenerational Inheritance
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Jennifer L. M. Thorson, Millissia Ben Maamar, Michael K. Skinner
The histone proteins that DNA is wrapped around create the nucleosome and can be chemically modified to alter gene expression (Figure 7.1). Histone proteins are often subject to post-translational modifications which form a complex molecular mechanism that subsequently results in regulation of gene expression and downstream biological functions (27). Numerous different histone post-translational modifications interact and generate combinatorial patterns to influence gene expression. Among the known histone modifications are lysine acetylation, lysine and arginine methylation, arginine citrullination, lysine ubiquitination, lysine sumoylation, ADP-ribosylation, proline isomerization, and serine/threonine/tyrosine phosphorylation (28).
The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Histone modifications include a number of chemical and physical changes to the histone proteins which contain a globular C-terminal domain and an unstructured N-terminal, and are responsible for packaging the DNA into nucleosomes. The N-terminal tails of the proteins can be modified by different post-translational covalent modifications including methylation, acetylation, ubiquitination, sumoylation, and phosphorylation on specific amino acid residues (Figure 11.14). These modifications work by either changing the accessibility of the chromatin, or by recruiting or obstructing non-histone effector proteins which decode the message encoded by the modification patterns, thus leading to either activation or repression of a gene.
Preclinical pharmacokinetics and metabolism of MAK683, a clinical stage selective oral embryonic ectoderm development (EED) inhibitor for cancer treatment
Published in Xenobiotica, 2022
Ji Yue (Jeff) Zhang, Jiangwei Zhang, Michael Kiffe, Markus Walles, Yi Jin, Joachim Blanz, Jerôme Dayer, Arevalo Sanchez, Chunye Zhang, Lijun Zhang, Ying Huang, Counde Oyang
Histone modification is one of the key epigenetic mechanisms in regulating many fundamental cellular processes. Polycomb Repressive Complex 2 (PRC2) is a key transcriptional repressor that plays an essential role in regulating gene expression through its lysine methyltransferase activity on histone H3 lysine 27 (H3K27) (Xu et al. 2010; Margueron and Reinberg 2011). The functional core of PRC2 that essential to catalyse the methylation of H3K27 consists of one of the SET-domain-containing histone methyltransferases enhancer of zeste (EZH2 or EZH1), embryonic ectoderm development (EED), suppressor of zeste (SUZ12), and the CAF1 histone-binding proteins RBBP4 and RBBP7. Dysregulation of PRC2 is observed in multiple human cancers. The catalytic subunit EZH2 is overexpressed in a wide range of human cancers and is associated with cell proliferation and poor prognosis in patients (Varambally et al. 2002; McCabe and Creasy 2014; Kim and Roberts 2016). Moreover, gain-of-function mutations in EZH2 have been implicated in follicular lymphoma, diffuse large B cell lymphoma, parathyroid carcinoma, and melanoma, while functionally similar mutations in EZH1 have been reported in autonomous thyroid adenomas. These mutations increase the methyltransferase activity of PRC2 thereby increasing the level of H3K27me3 in cells and aberrantly repressing gene expression (Audia and Campbell 2016).
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
Histones (H2A, H2B, H3, and H4) are proteins that assemble as an octamer (two of each) around which DNA wraps to form a nucleosome, the functional subunit of chromatin [82]. Chromatin typically exists in one of two major states – euchromatin and heterochromatin. While heterochromatin is tightly packaged and thereby more sterically restricted from transcriptional machinery, euchromatin has a more open conformation that is less condensed and more accessible to transcriptional complexes [82,83]. The transition between different chromatin states is partially mediated by histone modification. A major type of histone modification is acetylation/deacetylation. Histone acetylation can attract scaffolding proteins and enzymes involved in transcription. Enzymes that acetylate histones are termed histone acetyltransferases (HATs), and those that remove acetyl groups from histones are known as histone deacetylases (HDACs) [4,82–84]. Once histones are modified by acetylation, these changes need to be interpreted by other proteins for transcriptional regulation. Proteins that contain bromodomain (BRD) structures represent a class of proteins that can ‘read’ histone acetylation sites and indirectly regulate RNA polymerase II-mediated transcription [82,85].
Inhibition of histone demethylase JMJD1C attenuates cardiac hypertrophy and fibrosis induced by angiotensin II
Published in Journal of Receptors and Signal Transduction, 2020
Shenqian Zhang, Ying Lu, Chenyang Jiang
It is well known that histone modifications play key roles in gene transcription. Over the past decades, a great deal has demonstrated that histone methylation plays a key role in cardiac remodeling [7–9]. In our study, we identified a H3K9me2 and H3K9me1 demethylase JMJD1C involved in cardiac hypertrophy and fibrosis induced by pathological stress. JMJD1C is a global regulator of chromatin remodeling and gene expression. Gene expression is mediated by transcription factors and histone-modifying enzymes. Many different histone-modifying enzymes, including HDACs, HATs, HMTs, and HDMs, contribute to the dynamic regulation of chromatin structure and function, with concomitant impacts on gene transcription [28–30]. Unlike transcription factors that often have on-off effects on gene transcription, the effects of histone-modifying enzymes on gene transcription are often modulatory. This modulatory effect can be context- and gene-dependent such that only those genes exceeded the threshold will yield a phenotype and be identified. In our study, we did not identify what genes were different in JMJD1C knockdown and control cells, and which was regulated by histone methylation change. It will be interesting to identify these genes using RNA-seq and ChIP-seq combined analysis to further investigate the relationship between JMJD1C-regulated H3K9me2 marks which ultimately determines the transcriptional state of the gene as either active, repressed, or poised for activation.