In this issue of Epigenetics

Feedback Networks in Urological Tumors

Liep et al. review recent research that suggests that the mechanisms that control epigenetic modifications and microRNA function in urological tumors may be interrelated though a tightly regulated feedback network. The understanding of this network could help in the development of novel individualized therapies adjusted to the molecular pattern of a tumor.

Mitochondrial Regulation of the Nuclear Epigenome

Even though most pathogenic mitochondrial DNA mutations induce defects in mitochondrial oxidative phosphorylation, an increasing number of studies have identified an effect on the epigenetic landscape of the nuclear genome as a consequence of mitochondrial dysfunction. Minocherhomji et al. discuss how persistent pathogenic mutations in mitochondrial DNA may lead to reversible or irreversible changes in DNA methylation causing instability in the nuclear genome, which may play key roles in phenotypic variation related to mitochondrial diseases or dysfunction in cancer.

Global DNA Methylation by Fluorescence Polarization

Zhao and Xue have developed an accurate and sensitive method for high-throughput quantification of global DNA methylation from a large number of biological or clinical samples. This method, called FPDM, utilizes fluorescence polarization-based measurement of DNA methylation providing stable estimates of methylation level of submicrograms of DNA and appears more accurate than determination by gel electrophoresis.

Smyd3, H4K5me and Cancer

Smyd3 is a lysine methyltransferase implicated in chromatin and cancer regulation. Van Aller et al. now show that Smyd3 catalyzes histone H4K5 methylation. This novel histone methylation mark is detected in diverse cell types and its formation is attenuated by depletion of Smyd3 protein. Smyd3-driven cancer cell phenotypes require its enzymatic activity, suggesting Smyd3 as a potential new link between chromatin dynamics and neoplastic disease.

Developing Tools to Modify the Epigenome

Our ability to selectively manipulate gene expression by epigenetic means is limited. Two articles in this issue of Epigenetics present interesting new tools developed to achieve control over the epigenome. Gregory et al. developed a method aimed at achieving selective transcriptional activation by DNA demethylation. The authors present evidence that direct targeting of thymine-DNA-glycosylase (TDG) to specific sequences in the DNA can result in local DNA demethylation at potential regulatory sequences and lead to enhanced gene induction. This method could be used for the specific reactivation of epigenetically silenced genes in cancer cells. In another report, Rivenbark et al. employ a novel technology using artificial transcription factors (ATFs) to epigenetically target gene expression in cancer cells. The authors show that site-specific DNA methylation and long-term stable repression of the tumor suppressor Maspin and the oncogene SOX2 can be achieved in breast cancer cells via zinc-finger ATFs targeting DNA methyltransferase 3a (DNMT3a) to the promoters of these genes. These findings suggest that multimodular zinc-finger proteins linked to epigenetic editing domains can be used to alter gene expression patterns and stably reprogram cell fate.

Not all CTCF-Binding Sites are Created Equal

CTCF-binding sites are assumed to demarcate expression domains by promoting the formation of chromatin loops. Guibert et al. suggest here that such features may be context-dependent and show that the chromatin loop structures impinging on CTCF-binding sites within the maternal allele of the H19 imprinting control region (ICR) differ significantly. The authors suggest that the CTCF-binding sites within the H19 ICR are functionally diverse and organize context-dependent higher order chromatin conformations.

Retrotransposons as Source of Epigenetic Variation

Transcription of retrotransposons is usually repressed by DNA methylation, but a few elements escape this repression mechanism. The levels of this repression are also variable among individuals with an identical genome sequence, generating epigenetically different states of loci or epialleles. Ekram et al. identified candidate epialleles in the mouse genome showing variable levels of DNA methylation among individual mice of an isogenic background. Their results confirm the presence of a number of new retrotransposon-derived epialleles (and suggest the presence of more) and further identify retrotransposons as a major source of epigenetic variations in the mammalian genome.

5-mC in Non-Committed Cells

Recent studies imply that both 5-hmC and Tet1/2/3 proteins, catalyzing the conversion of 5-mC to 5-hmC, may play an important role in self renewal and differentiation of ESCs. Almeida et al. now assessed the distribution of 5-hmC in zebrafish and chick embryos and found that, unlike in mammals, 5-hmC is immunochemically undetectable in these systems before the onset of organogenesis. However, 5-hmC is enriched in later zebrafish and chick embryos and exhibits tissue-specific distribution in adult zebrafish. The authors conclude that 5-hmC enrichment of non-committed cells is therefore not a universal feature of vertebrate development.

Inducing CD1d Expression in Solid Tumor Cells

CD1d is a MHC class-like molecule that presents glycolipids to natural killer T (NKT) cells, regulating innate and adaptive immunity. Yang et al. investigated the regulation of the CD1d gene in solid tumors and found that histone deacetylase inhibitors can be used to induce CD1d gene expression in human and mouse cancer cells through the inhibition of HDAC1 and 2 and the activation of Sp1.

Genome-Wide DNA Methylation in Pediatric Rhabdomyosarcomas

Rhabdomyosarcoma is the most common soft-tissue sarcoma in children. Mahoney et al. have analyzed the methylation status of 25,500 promoters in normal skeletal muscle and in cell lines and tumor samples of embryonal and alveolar rhabdomyosarcoma from pediatric patients. The authors identified over 1,900 CpG islands that are hypermethylated in rhabdomyosarcomas relative to skeletal muscle. Cluster analysis revealed embryonal and alveolar subtypes had distinct DNA methylation patterns, with the alveolar subtype being enriched in DNA hypermethylation of polycomb target genes. These results suggest that DNA methylation signatures may aid in the diagnosis and risk stratification of pediatric rhabdomyosarcoma and help identify new targets for therapy.

Neonatal DNA Methylation and Maternal Psychiatric Care

Understanding the influence of maternal psychiatric illness and pharmacological exposures on the developing fetuses has critical implications for clinical care during pregnancy. Prenatal exposure to maternal psychiatric illness and psychiatric medication has been linked with adverse physiological, emotional and psychiatric development of the offspring. Several studies suggest that epigenetic mechanisms may facilitate these effects. Schroeder et al. explored the association between maternal psychiatric illness and treatment during pregnancy and neonatal DNA methylation patterns. The authors found no significant changes in neonatal DNA methylation attributable to maternal psychiatric diagnosis or depressive symptoms during pregnancy. This study therefore suggests that there are no large effects of maternal psychiatric illness, depressive symptoms or prenatal exposure to antidepressants on neonatal DNA methylation.

Submitted

02/07/12

Accepted

02/07/12