On the regulation of lysine methyltransferases, pp. 457–63
The molecular interactions between lysine methyltransferases and their substrates appear to be regulated by posttranslational modifications surrounding the lysine methyl acceptor. In this issue of Epigenetics, a timely review by Oliver Binda discusses the role of SET (Su(var)3–9, Enhancer-of-zeste, Trithorax) domain-containing lysine methyltransferases SET7 and SETDB1 in the crosstalk between two specific methyl-lysine sites (H3K4me3 prevents methylation by SETDB1 on H3K9, whereas H3K9me3 prevents methylation by SET7 on H3K4). The author also discusses how a similar crosstalk between posttranslational modifications regulates the function of non-histone proteins, such as the tumor suppressor p53 and the DNA methyltransferase DNMT1.
EZH2 in breast and prostate cancer, pp. 464–76
Overexpression of EZH2 and other PRC2 subunits, such as SUZ12, is associated with tumor progression and poor prognosis in several human malignancies. A review by Deb et al. in this issue of Epigenetics provides molecular insights into the essential role of EZH2 in breast and prostate tumorigenesis. The authors address the current understanding on the oncogenic role of EZH2 and also summarize how EZH2 has emerged as a promising therapeutic target in hormone-refractory cancers. The prospects for integrating EZH2 blockade with available pharmacological inhibitors are also discussed.
Lysine methylation in vivo, pp. 477–85
Lysine methylation mediated by methyltransferases occurs on multiple proteins throughout the cell. In this issue of Epigenetics, Cao et al. report on the development of pan-specific methyl-lysine antibodies that were utilized in immunoprecipitation experiments coupled with mass spectrometry to yield one of the first large-scale surveys of protein lysine methylation in vivo. The authors identified 552 lysine methylation sites, the large majority of which have not been yet reported. These sites showed significantly enriched sequence motifs, and resided in proteins that are involved in diverse biological processes, particularly in chromatin organization.
No aberrant hypermethylation of chromatin-modifying genes in ccRCC, pp. 486–93
Recent sequencing studies of clear cell renal cell carcinoma (ccRCC) have identified inactivating point mutations in the chromatin-modifying genes PBRM1, KDM6A/UTX, KDM5C/JARID1C, SETD2, MLL2 and BAP1. Now, Ibragimova et al. have sequenced the promoter region within a bona fide CpG island of PBRM1, KDM6A, SETD2 and BAP1 in bisulfite-modified DNA of a representative series of 50 primary ccRCC, 4 normal renal parenchyma specimens and 5 RCC cell lines in order to investigate whether aberrant hypermethylation is a mechanism of inactivation of these tumor suppressor genes in ccRCC. The authors report here that aberrant promoter hypermethylation of PBRM1, BAP1 and the other chromatin-modifying genes examined here is absent or rare in ccRCC.
Early Life Cadmium Exposure, DNA Methylation and Birth Weight, pp. 494–503
Dietary cadmium exposure was recently found to alter DNA methylation in adults. Now, Kippler et al. have evaluated associations between prenatal cadmium exposure, DNA methylation and birth weight. The authors investigated 127 mother-child pairs from rural Bangladesh, by measuring cadmium concentrations in mothers’ blood (gestational week 14) and children’s urine. Maternal cadmium exposure was associated with cord blood DNA methylation and this association was markedly sex-specific. The authors concluded that cadmium exposure in early life appears to alter DNA methylation differently in girls and boys, this being consistent with previous findings of sex-specific cadmium toxicity. Cadmium-related changes in methylation were also related to lower birth weight.
HLCS, MeCP2 and DNMT1 in the repression of LTRs, pp. 504–11
Holocarboxylase synthetase (HLCS) is a chromatin protein that has a role in the establishment of H3K9me gene repression marks through physical interactions with the histone methyltransferase EHMT-1. Previous studies suggest that the binding of HLCS to chromatin depends on DNA methylation. Xue et al. tested whether HLCS interacts physically with the DNA methyltransferase DNMT1 and the methyl CpG binding protein MeCP2 to facilitate the binding of HLCS to chromatin, and if these interactions contribute toward the repression of long-terminal repeats (LTRs) by H3K9me marks. The authors conclude that interactions between DNA methylation and HLCS are crucial for mediating gene repression by H3K9me, thereby providing evidence for epigenetic synergies between the protein biotin ligase HLCS and dietary methyl donors.
Chromatin remodeling of subtelomeres upon cellular senescence, pp. 512–21
Maintenance of telomere function appears to require the interplay between telomeres and subtelomeric chromatin. Thijssen et al. have now characterized chromatin remodeling of subtelomeres in relation to telomere shortening and cellular senescence, by systematically quantifying histone modifications and DNA methylation at the subtelomeres of chromosomes 7q and 11q in primary human WI-38 fibroblasts. Upon senescence, both subtelomeres showed a decrease in markers of constitutive heterochromatin, suggesting relative chromatin relaxation, but did not show increased levels of markers of euchromatin. While senescence-induced subtelomeric chromatin remodeling was similar for both chromosomes, chromatin remodeling at TERRA promoters displayed chromosome-specific patterns.
Genome-wide methylation and obesity, pp. 522–33
In this issue of Epigenetics, Xu et al. examine whether differential variability in methylation is an important feature of obesity.. The authors analyzed genome-wide methylation profiles of over 470,000 CpGs in peripheral blood samples from obese and lean African-American youth aged 14–20 y old. The authors identified a number of differentially variable CpG sites (DVCs), using statistics based on variances, as well as a substantial number of differentially methylated CpG sites (DMCs), using statistics based on means. Both the genes harboring DMCs and the genes harboring DVCs showed significant enrichment of genes identified by genome-wide association studies on obesity and related diseases, such as hypertension, dyslipidemia, type 2 diabetes and certain types of cancers, supporting their roles in the etiology and pathogenesis of obesity
DNA methylation in the insect Tribolium castaneum, pp. 534–41
Until now, no evidence of DNA methylation had been found in the red flour beetle, Tribolium castaneum. In this issue, Feliciello et al. report the detection of cytosine methylation in T. castaneum embryos by methylation sensitive restriction endonucleases and immuno-dot blot assay. DNA methylation in embryos is followed by global demethylation in larvae, pupae and adults and seems to proceed actively through 5-hydroxymethylcytosine, most probably by the action of TET enzyme. Cytosine methylation was not only restricted to CpG sites but was also found at CpA, CpT and CpC sites. In addition, complete cytosine demethylation of heterochromatic satellite DNA was induced by heat stress. DNA methylation is preserved within heterochromatin during development, indicating its role in heterochromatin formation and maintenance.
On the use of single archived dry blood spots for DNA sequencing, pp. 542–7
When using blood as biomaterial for methylome-wide association studies, the DNA is typically extracted directly from fresh or frozen whole blood that was collected via venous puncture. Now, Aberg et al. tested whether DNA extracted from dry blood spots may also be an alternative starting material for these kinds of studies. The authors report that DNA extracted from blood spots gives comparable results to DNA extracted from whole blood, showing that high quality methylome-wide investigations using MBD-seq can be conducted in DNA extracted from archived dry blood spots.
Enoxacin and the treatment of prostate cancer, pp. 548–58
Although efficient therapy is available for early-stage prostate cancer (PCa), treatment of advanced disease is mainly ineffective and remains a clinical challenge. Because miRNA dysregulation is associated with PCa development and progression, Sousa et al. have studied the usefulness of enoxacin as an anti-tumoral agent in PCa, due to its ability to induce miRNA biogenesis in TRBP-mediated manner. In a panel of five PCa cell lines (all wild type for TARBP2 and expressing TRBP protein), enoxacin was able to decrease cell viability, induce apoptosis, cause cell cycle arrest, and inhibit the invasiveness of cell lines. Enoxacin was also effective in restoring the global expression of miRNAs. Therefore, this study shows for the first time that PCa cells are highly responsive to the anti-tumoral effects of enoxacin.