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Epigenetics from Oocytes to Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Dagnė Daškevičiūtė, Marta Sanchez-Delgado, David Monk
H3K4me3 is a histone modification largely restricted to regions of DNA with unmethylated gene promoters that are transcriptionally active in embryos, similar to somatic tissues.13,46 Unlike histone acetylation, histone methylation does not change chromatin-DNA interactions by altering charge, but promotes binding of transcriptional activating TFs such as CHD1 and CFP1,47 whilst blocking transcriptional repressors including the NuRD complex.48 After fertilization in the mouse, H3K4me3 in the paternal genome is rapidly depleted while the noncanonical form covering promoter and distal sequences in the maternal genome persists until ZGA, upon which it is re-established with a canonical profile by the two-cell stage.40,44 Since H3K4me3 remodeling is rapid, this implies that yet to be identified oocyte-derived histone demethylase must be responsible for the remodeling. Unexpectedly, mapping H3K4me3 in human oocytes identified defined peaks in promoters, unlike the broad distribution defining the noncanonical profile, revealing that such patterns are not observed in humans.43
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
H3K4me3 is evolutionarily a highly conserved, effective histone modification in eukaryotes. The gene hallmark H3K4me3 is distributed across TSS and the promoter regions [13,18,19]. The work that has been done on yeast shows the association of SET1 with PAF complex. In addition, pol II initiation forms the Ser5-dependent phosphorylated that is deposited co-transcriptionally [20] (Figure 3.2). In addition, MLL and SETD1 recruitment to discrete target genes is usually mediated by means of various different cell-dependent specific transcriptional co-activators [18,19,21–23]. However, especially in higher organisms, the recruitment and establishment of more extensive H3K4me3 mechanisms are also highly at play.
DNA methylation, imprinting and gene regulation in germ cells
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Interaction between specific domains of the DNMT3 proteins and histones is generally regulated by specific modifications on histones. In vitro studies have demonstrated that methylation at lysine residue 4 of histone 3 (H3K4) inhibits binding of both DNMT3A and DNMT3L, whereas DNMT3A binding is promoted by trimethylation at lysine 36 of histone 3 (H3K36me3) (44). Further, it has been postulated that KDM2A, a demethylase of H3K36me2, binds to the unmethylated CpG sites, resulting in site-specific depletion of H3K36me2 (45). During embryonic cell differentiation, DNA methylation leads to the loss of KDM2A and acquisition of H3K36me2 (45). Unmethylated CGIs are enriched in H3K4me3, which leads to the blockage of DNMT3 interaction with DNA, thus protecting the DNA from de novo methylation (46–48). Apart from protecting DNA from getting methylated, H3K4me3 also mediates the availability of DNA for de novo methylation in oocytes. Enrichment of H3K4me3 on unmethylated CGIs depends on CXXC1 (CXX finger complex 1), which interacts with the Setd1 complex, which is a H3K4 methyltransferase. The expression of Setd1 in oocytes keeps H3K4 in the methylated state so that DNA remains in unmethylated condition (4). This condition mediates the DNA methylation machinery and free access to their target CGIs. Further, the requirement of methylation in H3K4 is necessary for the setup of DNA methylation in PGCs, as supported by a genetic study (49). The study showed that oocytes lacking KDM1B, a H3K4 demethylase, exhibited impairment in DNA methylation (49). It is also observed that in male germ cells, maternal imprinted gene DMRs are enriched in H3K4me2, suggesting a possible rationale between this modification and their protection from DNA methylation during spermatogenesis (50).
Epigenetic changes involved in hydroquinone-induced mutations
Published in Toxin Reviews, 2021
Minjuan Zeng, Shaopeng Chen, Ke Zhang, Hairong Liang, Jie Bao, Yuting Chen, Shiheng Zhu, Wei Jiang, Hui Yang, Yixian Wei, Lihao Guo, Huanwen Tang
Histone methylation is different from DNA methylation, as it is simply a marker of gene repression. Trimethylation of lysine 9 and lysine 27 of histone 3 (H3K9me3 andH3K27me3) is also a silencing marker, but trimethylation of lysine 4 of histone 3 (H3K4me3) is an activation marker that results in increased gene expression. Mancini et al. (2017) detected a distinctive signature combining repressive H3K27me3 and activating H3K4me3, indicating a tendency toward a poised chromatin conformation in the HL-60 cell line treated with HQ. These alterations were lost after short-term treatments, while long-term treatment resulted in a gradual increase in H3K4me3 and stable H3K27me3, most likely indicating increased activation of gene expression. Li et al. (2018) reported that H3K4me3 modification was significantly enhanced in benzene-exposed workers and was positively associated with the extent of DNA damage. Furthermore, the H3K4me3 marker was enriched in the promoters of several DNA damage responsive (DDR) genes, including CRY1, ERCC2, and TP53, in primary human lymphocytes (PHLCs) treated with HQ. In particular H3K4me3 correlated positively with expression of CRY1 in PHLCs from benzene-exposed workers. These outcomes suggest that H3K4me3 modification might mediate the transcriptional regulation of DDR genes in response to low-dose benzene (or HQ) exposure, which may be related to PARP-1 and γ-H2AX.
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).
Depletion of tumor-associated macrophages switches the epigenetic profile of pancreatic cancer infiltrating T cells and restores their anti-tumor phenotype
Published in OncoImmunology, 2018
Simone Borgoni, Andrea Iannello, Santina Cutrupi, Paola Allavena, Maurizio D'Incalci, Francesco Novelli, Paola Cappello
The status of T cells in cancer should be considered in the context of other immune cells, such as Tumor-Associated Macrophages (TAMs) or Myeloid-Derived Suppressor Cells (MDSCs).18 Both these populations are known to create an immune suppressive environment through either the secretion of cytokines such as IL10 and TGFβ, or the expression of inhibitory molecules such as PDL-1.19–21 This highly repressive environment inhibits the activation of CD8 T cells, and induces a switch of CD4 T cells towards T helper (Th)-2 and Treg phenotypes.22,23 However, the presence of mixed stimuli in the microenvironment creates conditions for reversible changes in infiltrating cells, including TILs. These modifications derive from the activation or inhibition of signaling pathways and chromatin remodeling. The histone modification landscape is highly involved in gene transcription control and can be affected by several modifications, such as acetylation, methylation and phosphorylation.24 In particular, specific histone modifications have been associated with gene transcription activation, such as tri-methylation of lysine 4 on histone 3 (H3K4me3), or repression, such as tri-methylation of lysine 27 on histone 3 (H3K27me3), and are known to rapidly change in response to environmental conditions.25