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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).
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
Further, this above idea is preferably supported by means of work, which shows that promoters due to lack of H3K36me2/3 highlighted mark, and also KDM2A/B, H3K36me2-dependent demethylases co-localize with H3 residue, H3K4me3 at the specific CpGI promoters, which ensure the active H3K36me2 removal from TSS [62,63]. Recognition of H3K36me2/3 is accompanied by PWWP domain, a protein motif, mostly found in various nuclear-based chromatin-dependent binding proteins [64–67]. Interestingly, all three members linked with H3K36-dependent methyltransferases belong to the NSD family, which catalyses H3K36me1/2, each having 2-PWWP domains and preferentially bind with H3 peptides, which contain H3K36me3 [66,67]. This indicates that recognition of H3K36me2/3 by means of its writers could be highly important for H3K36me1 propagation. Mono-/dimethylation of protein residue, H3K36, is specifically highly pervasive compared to the H3K36me3 and is not restricted to a region’s euchromatic domain or active transcription [68,69]. The recognizable biological functional role displayed by mono-/dimethylation has been unknown until now, though an H3K36me2 increase due to mutational changes in NSD2 has been directly associated with the upregulation mechanism of gene-dependent expression profiles in the case of tumors [70,71]. H3K36me2 may have crucial biological activity in its own right or may be necessary to serve the required substrate for successive SETD2-mediated trimethylation of H3K36. H3K36me3 and H3K36me2 distribution over active gene chromatin could also delay spreading and prevent silencing marks accumulation like H3K27me3 by directly inhibiting the PRC2, polycomb complex [72,73]. Histone methyltransferase, G9a, that controls in vivo functional activity of H3K9me2 predominantly represses the activity of genes at euchromatic regions [4].
Enasidenib for the treatment of relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase 2 mutation
Published in Expert Review of Precision Medicine and Drug Development, 2020
Mael Heiblig, Sabine Hachem-Khalife, Christophe Willekens, Jean-Baptiste Micol, Angelo Paci, Virginie Penard-Lacronique, Stéphane de Botton
D-2HG and αKG are highly similar molecules, differing only by the presence of a C2 hydroxyl group in D-2HG instead of the C2 carbonyl of αKG. D-2HG can occupy the same binding pocket as α-KG and acts as a weak competitive inhibitor of αKG dependent dioxygenases [29]. αKG as well as Fe2+ are used as cofactors of the activity of more than 60 αKG-dependent dioxygenases which are involved in a wide range of cellular processes such as hypoxia, angiogenesis, maturation of collagens of the extracellular matrix, DNA repair and regulation of epigenetics [30–34]. In vitro ectopic expression of IDH1/2 mutants produces high D-2HG levels that affect the activity of αKG-dependent dioxygenases including the DNA repair enzyme ALKBH [35], EGLN prolyl 4-hydroxylases [36], KDM4/JMJD2 and KDM2A/JHDM1A histone demethylases [5,29,37], the methyl-cytosine dioxygenases TET [6,29,38], and the first identified mRNA demethylase Fat mass and obesity-associated protein (FTO) [39,40]. The epigenetic deregulation induced by IDH2-mutant enzymes results in the impairment of key steps in histone, DNA and RNA demethylation and translates into chromatin and RNA hypermethylation. Such wide epigenetic modifications are associated with altered expression of genes involved in cellular differentiation, broad growth-suppressive activity in primary cells, or established cell lines [4,6,10,41,42] as in genetically engineering mouse models [8,9,15,43], thereby resulting in a block to cellular differentiation.
p300 Acetylates JHDM1A to inhibit osteosarcoma carcinogenesis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Yongkun Wang, Baozhen Sun, Qiao Zhang, Hang Dong, Jingzhe Zhang
JHDM1A (also called KDM2A or FBXL11) is a member of JmjC-domain-containing histone demethylase family [8]. Previous studies report that JHDM1A participates in the regulation of gene silencing, cell proliferation and cancer development via demethylate dimethyl histone H3 lysine 36 (H3K36me2) [9,10]. Histone methylation, including H3K36me2, has been demonstrated to exert key roles in the maintenance of genomic stability and the regulation of DNA repair [11]. Histone demethylation, including H3K36me2 demethylation, has been demonstrated to play critical roles in oncogenic reprogramming and cell proliferation regulation [12,13]. The imbalance between histone methylation and demethylation has been found to be associated with cancer tumorigenesis [14]. Wagner et al. indicated that JHDM1A could promote non-small cell lung cancer growth and metastasis by epigenetically activating ERK1/2 signaling [15]. Lu et al. reported that JHDM1A could promote the ovarian cancer development through modulating PI3K pathway and lowering epithelial-mesenchymal transition (EMT) process [16]. Whether JHDM1A participates in the occurrence and development of osteosarcoma is still needed to be explored.