The Genetic Program of Aging
Shamim I. Ahmad in Aging: Exploring a Complex Phenomenon, 2017
Histone methyltransferases and histone demethylases can dynamically regulate histone methylation. The global level or genomic distribution of a lot of histone methylations alters in organismal and cellular models of aging. The manipulation of histone methyltransferases and histone demethylases can modulate longevity of model organisms. Widespread changes in heterochromatin organization are found in mesenchymal stem cells derived from a Werner syndrome ESC model, including a generalized reduction of H3K9me3 (Zhang et al., 2015b). Targeted RNAi screens probing the effects of histone methyltransferases and demethylases on longevity in worms and flies have shown that H3K4me3 regulators can modulate life span (Jin, et al., 2011; Maures et al., 2011; Ni et al., 2012). Keeping the levels of another active histone methylation, H3K36me3, which is linked to transcriptional elongation, is required for healthy aging of worms and yeast. The mutation of the yeast RPH1 gene, which encodes a H3K36 demethylase, prolongs the yeast replicative life span, and yeast cells carrying H3 mutant forms that cannot be H3K36-methylated are short lived (Sen et al., 2015). In C. elegans, somatic levels of H3K36me3 moderately reduce with increasing age (Ni et al., 2012), and appear to be particularly decreased at genes that are deregulated with increasing age. Knock down of met-1 encodes the putative C. elegans enzyme depositing the H3K36me3 mark, shortening the life span in worms (Pu et al., 2015). These results suggest that the correct maintenance of H3K36me3 may be a key process during the senescent stage.
PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
PML/RARa behaves as a potent repressor of the RA signalling pathway (Fig. 10.1). The traditional model postulated that PML/RARa acted as a constitutive transcriptional repressor that altered the normal RARa signalling in APL cells, as the chimeric protein is unable to respond to physiological fluctuations of RA [42]. The transcriptional repression was shown to be the consequence of greatly enhanced binding to the SMRT/NCoR co-repressors and HDACs [23]. PML/RARa homodimerises and binds to DNA at the RARE sites even in the absence of its normal heterodimeric partner RXR. The homodimerisation is thought to enhance the binding of the physiological RARa interactors. Simplistically, enhanced corepressors binding depends upon the fact that the homodimer harbours two co-repressor docking sites and not just one as in RXR/RARa heterodimer, leading to a change in stoichiometry of association of PML/RARa with co-repressors and chromatin modifiers [39]. However, in addition, the formation of homodimers leads to the creation of novel binding interfaces. Histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3 is one of the chimera-specific partners responsible for imposing a heterochromatin-like structure on target genes, thereby establishing permanent transcriptional silencing [9]. Similarly, polycomb repressive complex 2 (PRC2) represents another example of a new PML/RARa interactor. It has been found that PRC2 is recruited to tumour suppressor genes causing and maintaining their silencing during the initial steps of PML/RARa driven leukaemogenesis [57].
Signal transduction and exercise
Adam P. Sharples, James P. Morton, Henning Wackerhage in Molecular Exercise Physiology, 2022
The tight packaging of DNA in chromatin must be unravelled before a gene can be transcribed. The packaging and unpackaging of DNA are known as chromatin remodelling and histone modifications are key mechanisms in the regulation of this process. Mapping of packaged and unpackaged DNA on a genome-wide scale has revealed that histone tail modifications are cell-specific and mark genes, transcription start sites and stretches of regulatory DNA, via which gene expression is regulated (53). Indeed, signal transduction pathways modulate chromatin remodelling by methylating (CH3, methyl group), acetylating (CH3CO, acetyl group) and phosphorylating histone proteins, especially in the tail regions of histones H3 and H4 (19, 20). The enzymes that catalyse these modifications include histone methyltransferases and histone demethylases as well as histone acetyltransferases and HDACs. The resultant modifications are abbreviated stating first the histone number, second the amino acid which is modified and finally the type of modification (ac stands for acetylation, me1, me2, m3 for methylation, dimethylation and trimethylation, respectively). For example, H3K27me3 refers to the trimethylation of lysine 27 (K is the one-letter abbreviation for lysine) of histone 3.
Chronic social defeat stress differentially regulates the expression of BDNF transcripts and epigenetic modifying enzymes in susceptible and resilient mice
Published in The World Journal of Biological Psychiatry, 2019
Alessandra Mallei, Alessandro Ieraci, Maurizio Popoli
Increasing recent evidence suggests that epigenetic mechanisms, such as histone post-translational modifications and DNA methylation, play an important role in mediating the gene expression changes induced by stressful experiences and the subsequent behavioural responses (Tardito et al. 2013; Bagot et al. 2014; Klengel and Binder 2015; McEwen et al. 2015). The best-characterized histone modifications are acetylation and methylation. Histone acetylation levels are controlled by the opposite activity of two classes of enzymes, histone acetyltransferases and histone deacetylases (HDACs), and acetylation is generally associated with active transcription. Histone methylation levels can increase or decrease genes expression, depending on the amino acids methylated and the number of methylated groups added. Methylation changes are regulated by histone methyltransferase and histone demethylase. On the contrary, DNA methylation normally represses gene transcription and is carried out by DNA methyl transferase proteins (Szyf 2009; Peter and Akbarian 2011; Sun et al. 2013; Tardito et al. 2013). However, it is still not well known whether CSD stress differentially modulates these enzymes in the HPC and PFC of resilient and susceptible mice.
Treating donor cells with 2-PCPA corrects aberrant histone H3K4 dimethylation and improves cloned goat embryo development
Published in Systems Biology in Reproductive Medicine, 2018
Tingchao Mao, Chengquan Han, Ruizhi Deng, Biao Wei, Peng Meng, Yan Luo, Yong Zhang
Histone methylation can lead to gene transcriptional activation and gene transcriptional silencing (Santosrosa et al. 2002). The main sites of histone H3 methylation are K4, K36, and K79. Set1 and Set2, which mediate the methylation of both H3K4 and H3K36, directly interact with RNA polymerase II (RNAPII) during the extension phase of mRNAs (Li et al. 2003; Robert et al. 2003). Histone methyltransferases (HMTs), the enzyme complex that mediates ubiquitination of histone H2B is also associated with RNAP II (Xiao et al. 2005). H2B ubiquitination is a prerequisite for the methylation of H3K4 and H3K79, suggesting that H3K79 is also involved in gene transcriptional activation. Furthermore, the association of histone methyltransferases Set1 and Set2 with RNAPII means that the methylation of genes H3K4 and H3K36 is the consequence of gene activation. Methylation of H3K4 or H3K36 can maintain the state of transcriptional activation when some of the transcription factors are down-regulated or absent. The distribution of the H3K4 methylated sites in different organs was analyzed, and H3K4me2 and H3K4me3 both showed high levels of transcriptional activity (Santosrosa et al. 2002). However, their distributions were not entirely overlapping. Dimethylation generally occurs at the entire gene segment, while trimethylation occurred at the 5ʹend of these genes (Bernstein 2006).
The role of pharmacogenomics in adverse drug reactions
Published in Expert Review of Clinical Pharmacology, 2019
Ramón Cacabelos, Natalia Cacabelos, Juan C. Carril
Mechanistic genes encode receptors and their respective subunits, synthesizing and catalyzing enzymes, and messengers involved in the mechanism of action of a particular drug. In the case of epigenetic drugs, mechanistic genes are those encoding components of the epigenetic machinery: (i) DNA methyltransferases (DNMTs)(DNMT1, DNMT3A, DNMT3B), which are the targets of nucleoside analogs, small molecules and natural products with DNA methyltransferase inhibitory activity; (ii) DNA demethylases (the ten-eleven translocation (TET) family, the AID/APOBEC family, and the BER (base excision repair) glycosylase family); (iii) histone deacetylases, the target of HDAC inhibitors (short-chain fatty acids, hydroxamic acids, cyclic peptides, benzamides, ketones, sirtuin modulators); (vi) histone acetyltransferases, (v) histone methyltransferases (lysine and arginine methyltransferase), (vi) histone demethylases, (vi) chromatin-associated proteins (ATP-dependent chromatin remodeling complexes): the SWI/SNF (switching defective/sucrose nonfermenting) family, the ISWI (imitation SWI) family, the CHD (chromodomain, helicase, DNA binding) family, and the INO (inositol requiring 80) family), and associated proteins (DOT1L, EZH2, G9A, PRMTs), (vii) Bromodomains, (viii) Chromodomains, and (ix) other components of the epigenetic machinery [26].
Related Knowledge Centers
- Catalysis
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