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Statistical Physics and Thermodynamics Primer
Published in Thomas M. Nordlund, Peter M. Hoffmann, Quantitative Understanding of Biosystems, 2019
Thomas M. Nordlund, Peter M. Hoffmann
Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.1
Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Molecular mechanisms that link IDH1/2 driven epigenetic dysfunction and tumorigenesis have been a subject of intensive investigations. Flavahan et al. (2016) revealed that IDH1 mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, which inhibits CTCF binding to its target regions. CTCF is a chromosomal organizer protein that functions as an insulator. CTCF loss alters chromosomal topology and permits a constitutive enhancer to interact with PDGFRA, a prominent oncogene in glioma, thereby driving aberrant PDGFRA activation to promote tumorigenesis. Inoue et al. (2016) found that IDH1R132H impaired DNA damage response (DDR) in hematopoietic stem cells. Mutant IDH1 triggered a genome-wide rise in repressive histone marks H3K9 and H3K27. In particular, H3K9me3 enrichment contributes to down-regulation of ATM,an upstream kinase that initiates the activation of DDR, thus impairing DDR pathway. A recent comprehensive epigenetic characterization of IDH1-mutant immortalized human astrocytes (IHAs) and patient-derived glioma tumorspheres demonstrated that IDH1R132H reshaped the chromatin landscape, as evidenced by progressive enrichment of H3K4me3, H3K36me3, H3K9me3 and H4K20me3 (Turcan et al., 2018). Moreover, DNA methylation array also showed a majority of differentially methylated CpG loci (67.4%) in IDH1R132H cells has increased methylation. Some of these epigenetic alterations was found to persist even after genetic ablation of IDH1R132H, indicating that long term IDH1R132H exposure leads to irreversible epigenetic alterations. Thus, IDH inhibitors should be used in conjunction with epigenetic drugs to fully reverse malignant phenotypes in IDH1-mutant cancers. Besides DNA and histone hypermethylation, Su et al. (2018) first discovered that R-2-hydroxyglutarate can also promote global N-methyladenosine (mA) RNA modification by suppressing the RNA demethylase Fat mass and obesity-associated (FTO) protein in IDH-wildtype cancer cells. Increased mA modification decreases the stability of MYC/CEBPA transcripts, leading to suppression of MYC signaling. Hence, 2-hydroxyglutarate has disparate functions in IDH1/2-wildtype and IDH1/2-mutant cancers. Collectively, these studies imply that mutant IDH1/2 function as driver mutations in certain cancer subtypes and mediate their oncogenic effects through modification of the epigenetic landscape.
Transgenerational male reproductive effect of prenatal arsenic exposure: abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse
Published in International Journal of Environmental Health Research, 2022
Guoying Yin, Liting Xia, Yaxing Hou, Yaoyan Li, Deqing Cao, Yanan Liu, Jingshan Chen, Juan Liu, Liwen Zhang, Qiaoyun Yang, Qiang Zhang, Naijun Tang
H19 and Igf2 are expressed in a monoallelic fashion from the maternal and paternal chromosomes, respectively. Methylation of H19 DMR and Igf2 DMR2 plays a critical role in Igf2 and H19 allelic transcription. On the maternal allele, CTCF insulator binds to the unmethylated H19 DMR and blocks the access of enhancer to the Igf2 promoter, resulting in H19 expression and Igf2 repression. On the paternal allele, H19 DMR is methylated and binding of CTCF is blocked, thus inactivating H19 and promoting Igf2 expression (Doshi et al. 2013). DMR2 is an Igf2 enhancer located in the sixth exon and a deletion of DMR2 could reduce Igf2 mRNA expression level (Murrell et al. 2001). In our study, hypomethylation of H19 DMR in testis occurs among arsenic-treated lineage mice, thus resulting in H19 overexpression. Although both H19 DMR and Igf2 DMR2 are hypomethylated, the mRNA expression levels of Igf2 in the testis are increased in arsenic-treated lineage. In addition to H19 DMR and Igf2 DMR2, Igf2 DMR0 and Igf2 DMR1 are also involved in the regulation of Igf2 expression. Constância et al. (2000) reported that deletion of DMR1 results in biallelic expression of Igf2. A recent study indicates that DMR0 is methylated on the active paternal allele in all tissues and may function similarly to mouse DMR1 (Murrell et al. 2008). It has been reported that exposure of mouse preimplantation embryos to 2,3,7,8-tetrachlorodibenzo-pdioxin, or TCDD, increased the methylation of Igf2/H19 imprint control region and decreased the mRNA expression of imprinted genes Igf2 and H19 (Wu et al. 2004). The heterogeneity of Igf2 expression may be caused by different environmental exposures and further studies are needed to clarify the interaction between methylation/expression defects of H19 and Igf2 of prenatal arsenic exposure.