A Centromere-Specific Chromatin Structure
The kinetochore, formed on centromeric DNA, interacts with microtubules from the mitotic spindle to achieve accurate chromosome segregation during mitosis. Its position is specified by sequence-independent epigenetic mechanisms. Most recent work on kinetochore specification has focused on the centromere-specific histone H3-variant CENP-A. To understand centromeric chromatin structure in more detail, Fukagawa has now focused on additional centromere proteins that have an intrinsic DNA binding activity and identified the DNA binding CENP-T-W-S-X complex. This complex is composed of four histone-fold domains with structural similarity to nucleosomes, displays DNA supercoiling activity and is essential for functional kinetochore assembly in vertebrate cells.
Ski and Cortical Development
The proto-oncogene Ski is a transcriptional regulator linked to the human 1p36 deletion syndrome, which involves a set of phenotypes including nervous system defects. Ski is likely to play a role in various pathways given its ability to interact with different signaling molecules to modulate the transcriptional activity of target genes. Ski regulates proliferation and differentiation of various cell types and is involved in the specification of cortical projection neurons. Baranek and Atanasoski now discuss the role of Ski as an essential linker between sequence-specific transcription factors and non-DNA binding cofactors with chromatin modifying activities, and hypothesize that the diverse functions of Ski as a co-repressor might be related to its association with distinct HDAC complexes.
On the Role of Global Heterochromatin Loss During Aging
Many theories exist that attempt to explain aging, including a role for free radicals, loss of heterochromatin, genetically programmed senescence, telomere shortening, genomic instability, nutritional intake and growth signaling. In an enlightening Point-of-View article, Tsurumi and Li highlight recent progress on the “loss of heterochromatin” model of aging and propose that epigenetic changes contributing to global heterochromatin loss may underlie the various cellular processes associated with aging.
On the Effects of Folic Acid Concentrations in Cell Culture Media
Folate and selenium may modulate DNA methylation patterns by affecting intracellular levels of the methyl donor S-adenosylmethionine (SAM) and/or the product of methylation reactions S-adenosylhomocysteine (SAH). Charles et al. have cultured fibroblasts and colon epithelial cells in the presence of different forms of folate or selenium and measured their effects on LINE-1 methylation, gene-specific CpG island (CGI) methylation and intracellular SAM:SAH. At physiologically-relevant doses, they identified no effects on LINE-1, CGI methylation or intracellular SAM:SAH. However, the commercial cell culture media used for the selenium studies, which contains supra-physiological concentrations of folic acid, induced LINE-1 hypomethylation, CGI hypermethylation and a decrease in intracellular SAM:SAH in both cell lines.
SIRT1-Mediated Deacetylation of MeCP2 and BDNF Expression
Methyl-CpG binding protein 2 (MeCP2) binds methylated cytosines at CpG sites on DNA and it is thought to function as a critical epigenetic regulator. Mutations in the MeCP2 gene have been associated to Rett syndrome, a human neurodevelopmental disorder. Zocchi and Sassone-Corsi now show that MeCP2 is acetylated by p300 and that SIRT1 mediates its deacetylation. SIRT1 has been shown to play a critical role in synaptic plasticity and memory formation. This study reveals a functional interplay between two critical epigenetic regulators, MeCP2 and SIRT1, which controls MeCP2 binding activity to the brain-derived neurotrophic factor (BDNF) promoter in a specific region of the brain.
Biomarkers for Detection and Prognosis of Breast Cancer
Jeschke et al. have performed a genome-wide screen for functional methylation changes in breast cancer in order to identify effective biomarkers. The authors identified a subset of candidate hypermethylated genes and validated them in primary breast cancers, testing them as markers for detection and prognosis prediction of the disease. These cancer-specific methylated genes were divided into two categories: highly frequent methylated genes that detect early stages of breast cancer and genes that show stage-dependent methylation frequency pattern, which are candidates to help delineate breast cancer prognostic signatures.
Promoter Methylation in Thyroid Cancer
Brait et al. comprehensively studied the promoter methylation profile of a panel of novel and known methylation markers for a cohort of thyroid lesions and adjacent benign thyroid. Among their results, the authors observed significantly higher methylation frequency and level for KIF1A and RARß2 in cancer samples compared with benign tumors. They also identified a negative correlation between BRAF mutation and RASSF1A methylation, and a positive correlation with RARß2 methylation. The authors suggest that integration of genetic and epigenetic changes in thyroid cancer will help identify relevant biologic pathways that drive the development of the disease.
Cigarette Smoking and DNA Methylation
Alpha-1 antitrypsin (AAT) deficiency and tobacco smoking are confirmed risk factors for Chronic Obstructive Pulmonary Disease. Because variable DNA methylation could be associated with smoking and inflammation, as reflected by the level of C-Reactive Protein (CRP) in AAT-deficient subjects, Siedlinski et al. have studied the methylation levels of 1,411 autosomal CpG sites in 316 subjects. In their study, the authors identified multiple potential candidate CpG sites associated with ever-smoking and CRP level in AAT-deficient subjects.
Epigenetic Change During Early Pregnancy
White et al. compared the methylation patterns of 27,578 CpG sites in 14,495 genes in maternal leukocyte DNA in early pregnancy, in postpartum and in nulligravid women. The authors concluded that early pregnancy may be characterized by widespread hypomethylation compared with non-pregnant states and that there is no apparent permanent methylation imprint after a normal term gestation. Nine potential candidate genes were also identified as differentially methylated in early pregnancy and may play a role in the maternal adaptation to pregnancy.
Mom’s Depression, Baby Birth Weight and DNA Methylation
Depressed mood in pregnancy has been linked to low birth weight, a risk factor for adult-onset chronic diseases in offspring. Liu et al. have now examined maternal depression in relation to birth weight and evaluated the role of DNA methylation at regulatory sequences of imprinted genes in this association. Among other findings, the authors reported that depressed mood was associated with a more than 3-fold higher risk of low birth weight and a 2.4% higher methylation at the MEG3 DMR.
Species-Specific Embryonic Chromatin Marks
During early embryonic development, dramatic changes in cell potency and chromatin organization occur. Because the role of histone variants in the context of chromatin remodeling needs further study, Bošković et al. have investigated the dynamics of acetylation of H2A.Z and two other active chromatin marks, H3K9ac and H3K36me3, throughout murine and bovine pre-implantation development. The authors present results that suggest that 'canonical' active chromatin marks exhibit dynamic, stage- and species-specific behavior in embryonic nuclei. They hypothesize that chromatin of early embryonic nuclei is subject to fine-tuning through differential acquisition of histone marks, allowing for proper chromatin remodeling and developmental progression in a species-specific fashion.
Naturally Occurring endo siRNA and LINE-1 Silencing
LINE-1 retrotransposons are capable of generating deleterious mutations by inserting themselves into genes. In normal cells, the activity of LINE-1 retrotransposon is mostly repressed, maintaining a stable genome structure. In contrast, cancer cells are characterized by aberrant expression of LINE-1 retrotransposons, which have the potential to contribute to genomic instability. The mechanistic pathways that regulate LINE-1 expression remain unclear. Chen et al. identified a subset of differentially expressed endo-siRNAs that directly regulate LINE-1 expression through DNA methylation, suggesting a functional link between the expression of endo-siRNAs and LINE-1 retrotransposons in human cells.
Comparing MassARRAY and MSP
Assessment of DNA methylation has become a critical factor for the identification, development and application of methylation-based biomarkers. Claus et al. have systematically compared a quantitative high-resolution mass spectrometry-based approach (MassARRAY), pyrosequencing and the broadly used methylation-specific PCR (MSP) technique by analyzing clinically relevant epigenetically silenced genes in acute myeloid leukemia (AML). The authors conclude that, while MSP is still the most commonly applied technique for DNA methylation assessment, their data highlight advantages of quantitative approaches for precise characterization and reliable biomarker use of aberrant DNA methylation, particularly in primary patient samples.
RNAP V-Dependent siRNAs
In plants, heterochromatin is maintained by a small RNA-based gene silencing mechanism known as RNA-directed DNA methylation that requires the non-redundant functions of two plant-specific DNA-dependent RNA polymerases, RNAP IV and RNAP V. While RNAP IV plays a major role in siRNA biogenesis, RNAP V appears to recruit the DNA methylation machinery to target endogenous loci for silencing. Lee et al. have now characterized the RNAP V-dependent, heterochromatic siRNA-generating regions in the Arabidopsis genome. The authors showed that RNAP V-dependent siRNA-generating loci are associated predominately with short repetitive sequences in intergenic regions. Their results suggest that RNAP V affects siRNA production from genomic loci with features dissimilar to known RNAP IV-dependent loci and that, along with RNAP IV and DRM1/2, RNAP V may target and silence a set of small, intergenic transposable elements located in dispersed genomic regions for silencing.
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