Role of Histones in Cell Differentiation
Gerald M. Kolodny in Eukaryotic Gene Regulation, 2018
The role of histone methylation is most unclear. It has been supposed to increase the stability of the DNA-histone complex, thus changing the structure of chromatin.201 No relations between histone methylation and transcription were found, but attempts were made to relate this modification to the structural changes of chromatin during the cell cycle.201,202 It seems, however, that the higher histone methylation in G2 and mitosis203 is due to a dimethylation step.198 The constant molar ratios of different methyl derivatives in histones197 and their low turnover make less probable the hypothesis that methylation plays a role in mitotic condensation. It seems more probable that the increased methylation of histones during the cell cycles is related to the sequential methylation of newly synthesized histones.
The Parasite's Way of Life
Eric S. Loker, Bruce V. Hofkin in Parasitology, 2023
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.
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.
Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors
Published in Annals of Medicine, 2023
Moustafa M. Madkour, Wafaa S. Ramadan, Ekram Saleh, Raafat El-Awady
Histone methylation is the dynamic addition of one, two, or three methyl groups to specific amino acids within a histone protein. Nearly all biological processes, including DNA repair, cell cycle, stress response, transcription, development, differentiation, and aging, have been shown to be regulated by histone methylation [109]. Since abnormal histone methylation has been reported to play a causal role in tumorigenesis, it can be linked to anticancer-related drug responses [110]. Histone lysine demethylases (KDMs) are enzymes that catalyze the removal of methyl group from lysine and arginine residues on histone tails and were found to play critical roles in oncogenesis [111]. Addition of the KDM inhibitor 17-DMAG to the clinically tested combination vincristine and irinotecan significantly improved the efficacy of this combination, indicating that targeting KDM may serve as a useful approach for enhancing the response to anticancer drugs like Top I inhibitors [112].
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
A hallmark of pathological cardiac hypertrophy and fibrosis is the re-expression of fetal genes [2]. Epigenetic modifications are emerging regulators of this transcriptional reprograming [3–5]. Histone methylation is a conserved posttranslational modification, and regulates a multiple of genomic functions, including gene transcription [6]. Di- and tri-methylation of histone 3 lysine 9 (H3K9me2 and H3K9me3) are normally associated with transcriptional repressing and are silenced in hypertrophic and failing hearts in mouse and humans [7–9]. Histone methylation is dynamically controlled by lysine methyltransferases (KMTs) and lysine demethylases (KDMs). Zhang et al. reported that the H3K9me3 demethylase KDM4A/JMJD2A promoted pressure overload-induced LVH associated with activation of fetal genes re-expression [8]. Thienpont et al. reported that the H3K9me2 di-methyltransferase EHMT1/2 protected mice against pressure overload-induced LVH associated with activation of fetal genes re-expression [9]. Zhang et al. reported that the H3K9me2 demethylase KDM3A/JMJD1A promoted pressure overload-induced LVH associated with the activation of fetal genes re-expression [7]. Importantly, besides the H3K9me2/me1 demethylases JMJD1A, JMJD1C was also upregulated and positively associated with heart diseases [7,10,11]. However, its role in pathological heart diseases remains unknown.
Targeting the cell signaling pathway Keap1-Nrf2 as a therapeutic strategy for adenocarcinomas of the lung
Published in Expert Opinion on Therapeutic Targets, 2019
Bo Zhang, Zhiyuan Ma, Biqin Tan, Nengming Lin
Histone methylation plays a critical role in the regulation of chromatin compaction and gene expression. Hyperglycemia increased the binding of Sp1 at KEAP1 promoter, thus enriched H3K4me1 and activated Histone-lysine N-methyltransferase SetD7. On the contrary, SetD7-siRNA disturbed the binding of Sp1 at KEAP1 promoter, decreased Keap1 expression and promoted Nrf2-regulated antioxidant genes. Cessation of hyperglycemia failed to attenuate increased binding of Sp1 at KEAP1, and the promoter continued to be methylated with increased expression of KEAP1 and decreased expression of Nrf2-regulated genes [52]. Hence, Nrf2 signaling is controlled by the site-specific glycosylation of KEAP1, revealing a potentially broad link among nutrient sensing, proteostasis and stress resistance in both normal and cancer cells [53].
Related Knowledge Centers
- DNA
- Histone
- Methyl Group
- Amino Acid
- Chromatin
- Chromosome
- Nucleosome
- Long-Term Memory
- Animal Embryonic Development
- Neurodegenerative Disease