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Vitamin C in Immune Cell Function
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Abel Ang, Margreet C.M. Vissers, Juliet M. Pullar
DNA demethylation changes occur during development of monocytes into immature DCs and mature DCs [162]. TET2 represses late phase expression of DC pro-inflammatory molecules such as Il-6, MCP-1, and MCP-3 in response to LPS stimulation, and TET2 knockout results in a greater degree of inflammatory response in mice challenged with LPS and colitis [150]. KDM5B acts to repress type I IFN and other innate cytokines in DCs to promote an altered immune response following respiratory syncytial virus infection that contributes to development of chronic disease [163].
Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
A genome-wide RNAi screen for genes that regulate life span in C. elegans resulted in a number of genes encoding the SET domain containing histone methyltransferases [45]. Knockdown of set-2, set-4, set-9, set-15, and ash-2 extended the worm life span, ash-2 having the most significant effect. The encoded protein ASH-2 is a member of H3K4 trimethylation (H3K4me3) complex in yeast, flies, and mammals. In C. elegans, ash-2 knockdown decreases global H3K4me3 levels. WDR-5 is a protein that interacts with ASH-2 in mammals, and is important for the mono-, di-, and trimethylation of H3K4 both in C. elegans and mammals. The wdr-5 knockdown also decreases H3K4me3 levels and significantly (by ∼30%) extends life span in C. elegans. Thus, ASH-2 and WDR-5 mediated H3K4 trimethylation seems to promote aging and limit the life span in C. elegans. In mammals, ASH-2 and WDR-5 form a complex with several H3K4me3 methyltransferases of the SET1/MLL family. Of the four SET1/MLL orthologues in C. elegans, SET-1, SET-2, SET-12, and SET-16, only SET-2 affects the life span. The set-2 knockdown worms have reduced H3K4me3 levels. On the other hand, neither set-9 nor set-15 knockdowns affect global H3K4me3 levels, even though they both regulate the life span. The bacterially expressed SET-2 methyltransferase methylates histone H3 at lysine 4 in vitro to generate H3K4me2, whereas ASH-2 converts H3K4me2 to H3K4me3. Analysis of the life span-extending effects of combined mutations showed that ASH-2, WDR-5, and SET-2 act in the same pathway to limit the life span. RBR-2 is an H3K4me3 demethylase homologous to the human KDM5A and KDM5B—H3K4me3 demethylases of the JARID family. The rbr-2 mutant worms show increased H3K4me3 levels and a significantly decreased life span, indicating that RBR-2 activity is necessary for normal longevity. The ash-2 knockdown leads to changes in the expression of 220 genes at the larval stage L3 and of 847 genes at D5 (day 5) of adulthood. This set of ASH-2-controlled genes is most enriched for genes known to affect the life span and to change expression during aging. These results show that members of the H3K4me3 methyltransferase complex ASH-2 and of the H3K4me3 demethylase complex RBR-2 regulate aging by controlling the expression of a specific subset of genes.
Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Ben Sang, Jianjing Sun, Dongxu Yang, Zhen Xu, Yuzhen Wei
Histones are a class of basic proteins in eukaryocyte that consists of four members: H1, H2A, H2B, and H4. The function of histones on regulating gene expression is mainly dependent on its post-translational modification on the specific amino acid residues [10]. For the selected example, repressing the trimethylation of histone H3 at lysine 4 (H3K4me3) by demethylase KDM5B was related to defects in genome silencing [11]. Likewise, acetylation of histone H3 at lysine 27 (H3K27ac) increased the expression of transcription factors, including NRF1, GABPA, and MEF2A [12]. Histone H1.5 is a somatic subtype of the histone H1 variants that functions as a pivotal regulator in stabilizing chromatin structure, gene expression, DNA repair, and cell proliferation [13]. Moreover, histone H1.5 has been considered as a novel cancer marker as its expression is associated with various human cancers, like prostatic cancer [13], ovarian granulosa cell tumor [14], and leiomyoma [15].
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
Recently, Liu et al. reported that overexpression of Kdm5b, a H3K4me3 demethylase, has beneficial effects on cloned embryo development in mice (Liu et al. 2016). In addition, Liu et al. have successfully cloned cynomolgus monkeys after the injection of H3K9me3 demethylase Kdm4d mRNA and treatment with histone deacetylase inhibitor trichostatin A at the one-cell stage (Liu et al. 2018). These results support that view that histone modifications facilitate the cloned embryo development. Previous studies showed that treatment of reconstructed embryos with low cellular toxicity BIX-01294 and UNC0638 compounds failed to improve the development rates in vitro (Fu et al. 2012; Wang et al. 2017). Nevertheless, SCNT embryos treated with BIX-01294 or UNC0638 displayed the appropriate patterns of gene expression and epigenetic modifications (Huang et al. 2016; Wang et al. 2017). Previous studies have shown that SCNT embryos simultaneously suffer from low H3k9 acetylation (Bernstein 2006), excessive DNA methylation (Yang et al. 2007), and low H3K4 dimethylation (Shao et al. 2008). This suggested that multiple epigenetic modifications in SCNT embryos must be simultaneously corrected at the same time to ensure appropriate embryo development.
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
A chromatin environment that promotes transcription needs to be modified to reach a chromatin state that facilitates DNA repair in the presence of DNA damage. It has further been shown that H3K4me3, which is associated with transcriptional activation, is demethylated at DNA damage sites in human cells (Mosammaparast et al. 2013; Li X et al. 2014). KDM5B mediates demethylation of H3K4me2/me3 and also accumulates at I-Sce1-induced DSB sites in a PARP1 and macro-H2A1.1 dependent manner in human cells (Li X et al. 2014). Loss of KDM5B impairs the accumulation of the DSB repair factors Ku70 and BRCA1 at DSBs, which leads to defective NHEJ and HR repair. The functional role of mono- and di-methylation of H4K20 (H4K20me1/2) in DNA repair is well established. 53BP1 recognizes histone H4 lysine 20 methylation through its Tudor domain and is required for 53BP1 recruitment (Botuyan et al. 2006; Pei et al. 2011). In mammals, dimethylation of histone H4 lysine 20 (H4K20me2), is mediated by the histone methyltransferase MMSET (also known as NSD2 or WHSC1) (Pei et al. 2011). Interestingly, MMSET depletion significantly decreases H4K20 methylation at DSBs as well as 53BP1 accumulation at DSBs. Because histone H4K20 methylation is diluted by DNA replication, this hypomethylation of K20 may also serve to bias towards HR repair following DNA replication (Pellegrino et al. 2017). In addition, H4K20me2/3 is mediated by other KMTs (KMT5B/C or Suv4-20h1/2), which have also been shown to be involved in the DNA damage response (DDR). MEFs lacking these enzymes exhibit genome-wide transition to an H4K20me1 state, which results in increased sensitivity to DNA damaging agents and less efficient for DNA double-strand break (DSB) repair (Schotta et al. 2008).