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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 specific distribution leads to set2 association with plo11 component, elongating Ser2-dependent phosphorylated CTD, basically which is highly predominant over 30 ends and bodies of functional genes [56–58]. Similarly, H3K36me3 residue has also interlinked with the regulation of specific histone protein residue acetylation. Histone residue, H3K36me3, is able to recruit HDACs from active transcription regions. In yeast, H3K36me2/3 recognition by means of EAF3 complex containing bromodomain recruits the HDAC+RPD3S complex that deacetylates histones. In addition, it also prevents spurious initiation of transcription within bodies of active genes [59–61]. At the specific region of gene promoters, histone hyperacetylation and H3K4me3 might play a particular role in the regulation of transcriptional initiation from regions of transcriptional stating sites, whereby the H3K36me2/3-mediated process related with deacetylation is needed in the wake of specific active gene transcriptional machinery to prevent transcriptional initiation from inappropriate aberrant regions present within gene structure. Mutual exclusivity between the H3K36me3 and H3K4me3 may be crucial to maintain transcriptional integrity.
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).
Proteomic approaches for cancer epigenetics research
Published in Expert Review of Proteomics, 2019
Dylan M. Marchione, Benjamin A. Garcia, John Wojcik
A careful MS-based study elucidated the mechanism underlying translocation-associated MM by first clarifying that the principal intracellular byproduct of NSD2 was H3K36me2. Moreover, the authors showed that expression of a single copy of the fusion gene was sufficient to increase cellular H3K36me2 approximately threefold. ChIP-seq revealed that the fusion gene also significantly disrupted the genomic distribution of H3K36me2. Correlation of the ChIP-seq data with microarray gene expression data demonstrated that the genes with the greatest gain of H3K36me2 were also the most upregulated, and this gene set was significantly enriched for genes in numerous cancer pathways. Accordingly, expression of a constitutively active form of NSD2 was sufficient to promote increased proliferation, anchorage-independent growth, and xenograft tumor formation in t(4;14) negative myeloma cells. Thus, the proteomic analysis of histone PTM patterns was a critical first step toward determining the oncogenic mechanism of t(4;14) translocation-driven MM [64].
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
H3K36me2 is an important histone modification pathway in cells [33]. It exerts critical function in maintaining genomic stability and participates in the regulation of DNA repair [9,33]. Aberrant demethylation of H3K36me2 has been demonstrated to contribute to cancer development [34,35]. JHDM1A can demethylate H3K36me2 and play a tumor-promoting role in tumor cells [10,35]. Herein, we discovered that acetylation of JHDM1A (that could cause by p300) disrupted its binding to nucleosomes and thereby impaired its ability to demethylate H3K36me2. More importantly, the transcription of p21 and puma were both increased in osteosarcoma cells after mimicking of JHDM1A acetylation, which induced the mRNA expression levels of p21 and puma were enhanced in osteosarcoma cells. p21 is a cyclin-dependent kinase (CDKs) inhibitor that can cause cell-cycle arrest by interacting with different stimuli such as p53, CDKs, proliferating cell nuclear antigen (PCNA) and estrogen receptor-α (ER-α) [36]. Puma is a member of the “BH3-only” branch of the Bcl-2 family localized in the mitochondria [37]. It can trigger mitochondrial dysfunction-mediated cell apoptosis through antagonizing the functions of Bcl-xl and myeloid cell leukemia-1 (Mcl-1) [38]. Both p21 and puma are lowly expressed and present tumor suppressive activities in cancer cells, including osteosarcoma cells [39,40]. Herein, we found that acetylation of JHDM1A up-regulated the mRNA expression levels of p21 and puma in osteosarcoma cells, which implied that p300-dependent acetylation of JHDM1A could inhibit osteosarcoma carcinogenesis. Moreover, further experiments were done to evaluate the acetylation of JHDM1A on osteosarcoma cell proliferation and invasion, as well as tumor growth. We found that acetylation of JHDM1A suppressed the proliferation and invasion of osteosarcoma HOS cells, as well as inhibited the tumor growth in vivo.
Epigenetic biomarkers in colorectal cancer: premises and prospects
Published in Biomarkers, 2018
Mozhdeh Zamani, Seyed Vahid Hosseini, Pooneh Mokarram
Nucleosomal core histones are the primary protein components of chromatin, which control the DNA compaction and gene expression. Each nucleosome consists of 147 bp of DNA wrapped around the histone octamer including two copies of four core histones, H2A, H2B, H3 and H4. All of the core histones have specific tails, which can be subjected to different modifications consisting acetylation, methylation, ubiquitination, phosphorylation and sumoylation. Three-dimensional structure of the nucleosome is altered through these post-translational modifications and transcriptional control of related genes are affected by creating two conformations of compacted, inactive heterochromatin, or active open euchromatin (Xia et al.2014). For instance, acetylation of H3 and H4 and also di- and tri-methylation of H3 lysine 4 and H3 lysine 36 (H3K4me2, H3K4me3, H3K36me2 and H3K36me3) are enriched in euchromatin and lead to transcriptional activation. In contrast, inactive transcriptional state is identified by trimethylation of H3 lysine 9 and 27 (H3K9me3 and H3K27me3) in heterochromatin (Baylin and Jones 2011). Various studies have demonstrated dysregulation of histone modifications in different malignancies such as CRC due to alterations in genes associated with histone modifications processes. In this regard, there are different reports of aberrant expression of histone deacetylases (HDAC1/HDAC2) (Weichert et al.2008), mutation of the histone acetyltransferases genes such as P300, CBP and PCAF (Özdağ et al.2002, Ionov et al.2004) and overexpression of histone methyltransferases like EZH2 in CRC (Esteller 2007, Wang et al.2010). Despite various efforts to identify the potential application of histone modifications as new class of biomarkers, limitations of the technical assay which detect the post-translational modifications, make it difficult to determine these alterations in the primary cancer tissues. However, in spite of these limitations, a number of studies explored aberrant histone modifications as potential biomarkers. For instance, low levels of H3K9me3, H4K20me3 (Benard et al.2014), H3K27me2 (Tamagawa et al.2013) and H3K56ac (Benard et al.2015) and also high levels of H3K4me3 indicate poor prognosis in CRC patients (Benard et al.2014). It has also been demonstrated that, low levels of H3K9me3 and H4K20me3 can be used as potential diagnostic biomarkers for CRC (Leszinski et al.2012, Gezer et al.2013).