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Mother and Embryo Cross Communication during Conception
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Anna Idelevich, Andrea Peralta, Felipe Vilella
Histone modification is another epigenetic mechanism. Histones are basic proteins acting as spools around which DNA winds, packaging it into structural units, called nucleosomes. A histone octamer consisting of two copies of each of the four core histones (H2A, H2B, H3, and H4), around which approximately 146 bp of the DNA winds, comprises a nucleosome. It has been shown that histones are subject to numerous covalent modifications, including methylation, acetylation, phosphorylation, sumoylation, glycosylation, and ubiquitination, at specific tails of selected amino acids. A number of enzymes are involved in this process, including histone methyltransferases (HMTs), acetyltransferases (HATs), kinases, and ubiquitin ligases functioning as writers, as well as erasers, such as histone demethylases, deacetylases (HDACs), and phosphatases, capable of removing modification marks from the histone tails. These modifications impose either transcriptionally repressive or transcriptionally permissive chromatin structures. For instance, histone acetylation usually results in active genes as does the di- or trimethylation of lysine residue 4 in histone H3 (H3K4me2, H3K4me3), whereas H3K9me2/3 and H3K27me3 modifications repress gene expression. In general, unlike DNA methylation, which is believed to confer a more stable and long-term silencing mechanism, various histone modifications seem to exert short-term, flexible regulation important for the plasticity of development [140–144].
Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Gene expression regulation by means of histone-modifying enzymes marks a dominant mechanism that regulates the differentiation and development of cells. Posttranslationally, modifications of histones could be carried out by methylation, acetylation, phosphorylation, ubiquitination, and sumoylation [75]. In particular, methylation at lysine residues of histone protein is the chief regulator of active gene expression. MLL1-dependent H3K4me3 and EZH2-dependent H3K27me3 EZH2, H3K27me3, are the foremost well-known modifications that are strongly related to recognizable gene expression also with repression [76–80]. Various other specific histone-methylation regions have been recognized to be more critical, including H3K9 histone residue with G9a-dependent H3K9me2 and Suv39h (1–2)-mediated H3K9me3. All these display crucial functional roles in cellular differentiation and functions, too [81–84]. Available data suggest that H3K9me2 has also been found to modify euchromatin. In addition, it also is dynamically able to regulate the gene expression of many differentiating cells.
Epigenetic Reprogramming in Early Embryo Development
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Drastic changes of the histone tail modifications during the preimplantational period have been reported and detailed information is available in recent reviews by different authors including ourselves (7,83–85). Briefly, histone remodeling starts, just after sperm-egg fusion, with the replacement of protamines by oocyte-derived histones in the sperm, which entails an epigenetic asymmetry between pronucleus, with an initial predominance of acetylated and unmethylated histones in the spermatozoa. Overall, modifications associated with gene repression (H3K27me3, H3K9me2/me3) are deleted and there is an increase of activation marks (H3K4me3), concomitant with pluripotency acquisition. Later, inhibitory and other histone marks are reacquired at the initial steps of differentiation in the late blastocyst, showing asymmetrical distribution between ICM and TE although these differences are not directly correlated with gene transcription (86).
The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy
Published in Expert Opinion on Drug Discovery, 2019
Najah Albadari, Shanshan Deng, Wei Li
BIX01294 (2) is a diazepinquinazolin-amine derivative that was originally identified as an Euchromatic histone-lysine N-methyltransferase 2 (EHMT2)/G9a inhibitor during a chemical library screening of small molecules [117]. EHMT2 is an essential enzyme that catalyzes the methylation of histone H3 at lysine residue 9 to form H3K9me2, which is an epigenetic marker [118,119]. EHMT2 is highly expressed in human cancer cells such as in neuroblastoma and glioblastoma brain cancers and BIX01294 was reported to decrease the proliferation of neuroblastoma cells. BIX01294 was also reported to decrease HIF-1 expression in HepG2 human hepatocellular carcinoma cells via increasing the hydroxylation of HIF-1α by increasing PHD2 and pVHL expressions and thus diminishing HIF-1α stability (at 1 μM range) [120]. However, it is noteworthy that G9a inhibition was reported to upregulate the HIF-1α and HIF-2α in breast cancer cells after using higher concentrations of BIX01294 [121].
The relationship between histone posttranslational modification and DNA damage signaling and repair
Published in International Journal of Radiation Biology, 2019
Ajit K Sharma, Michael J. Hendzel
H3K9me3 has been associated with heterochromatin and transcription repression (Bannister et al. 2001; Pei et al. 2011). H3K9me3 specific KMTs accumulate at DNA damage sites and mediate the local enrichment of H3K9me2/me3 in human cells (Sun et al. 2009; Ayrapetov et al. 2014; Khurana et al. 2014; Alagoz et al. 2015). Enrichment of H3K9me3 at DNA damage sites perform several functions during DNA damage response (DDR). For example TIP60, histone acetyltransferase can directly bind to H3K9me3 at damaged sites through its chromodomain (Sun et al. 2009). This interaction increases the HAT activity of TIP60, which further activates ATM by acetylation (Sun et al. 2009; Tang et al. 2013).
Molecular and epigenetic modes of Fumonisin B1 mediated toxicity and carcinogenesis and detoxification strategies
Published in Critical Reviews in Toxicology, 2021
Thilona Arumugam, Terisha Ghazi, Anil A. Chuturgoon
FB1 can also affect chromatin architecture and gene expression through modifications to histones. Histone modifications are covalent post-translational modifications that can influence chromatin structure and subsequently the transcriptional status of genes. Histone modifications include the methylation, acetylation, phosphorylation, SUMOylation, and ubiquitination of specific amino acid residues (Cosgrove et al. 2004). In FB1-treated NRK-52E cells (25, 50, and 100 µM), a global increase in di- and tri-methylation of lysine 9 on histone 3 (H3K9me2/3) was accompanied by an increase in the H3K9 histone methyltransferase (HMT). However, high doses (50 and 100 µM, 24 h) and prolonged exposure (25 µM, 27 and 96 h) to FB1 significantly reduced methylation of lysine 20 of histone 4 (H4K20) (Sancak and Ozden 2015). Similar results in H3K9me3 and H4K20me3 were observed in the foetus of methyl deficient dams exposed to FB1 (Pellanda et al. 2012). Both H3K9me3 and H4K20me3 establish a condensed and transcriptionally inert chromatin conformation that contributes to the maintenance of genome stability (Saksouk et al. 2015). Loss of H4K20me3 provokes genome instability and is considered a hallmark of cancer (Van Den Broeck et al. 2008); the rise in H3K9me3 might be the defence mechanism promoting the cell to resist heterochromatin disorganization by FB1 (Pellanda et al. 2012). These changes in H3K9 methylation are associated with closed chromatin and inhibition of transcription, further pointing to the probability that FB1 silences genes especially, tumour suppresser genes (Sharma et al. 2010). However, the study by Chuturgoon et al. (2014a) indicated that FB1 significantly increased the expression of two histone demethylase genes KDM5B and KDM5C, which may promote H3K4me3/me2 demethylation. But this was not the case in NRK-52E cells and in a recent study which used HepG2 cells (Sancak and Ozden 2015; Arumugam et al. 2020). Regarding histone acetylation, FB1 had little effect on H4K16 and H3K18 acetylation (Pellanda et al. 2012; Gardner et al. 2016). A dose and time-dependent decrease was observed in the H3K9ac levels in response to FB1, while histone acetyl transferase activity was only inhibited as a consequence of prolonged exposure (96 h) (Sancak and Ozden 2015). In LM/Bc embryonic fibroblasts, the elevation in Sa1P after FB1-mediated inhibition of CS, inhibited histone deacetylase activity, promoting histone acetylation of H2NK12, H3K9, and H3K23 (Gardner et al. 2016). The results of this study along with Pellanda et al. (2012), provides a potential mechanism for the failure of neural tube closure observed in mice and humans following FB1 exposure. However, further in vitro studies should be undertaken to confirm this hypothesis. Histone phosphorylation also contributes to the toxicity of FB1. Downregulation in the phosphorylation of γ-H2AX was observed upon FB1 (200 µM, 24 h) exposure in HepG2 cells (Chuturgoon et al. 2015). Poor phosphorylation of γ-H2AX provokes genome instability and prevents appropriate responses to DNA damage leading to gene mutations and tumourigenesis (Podhorecka et al. 2010).