Blood Spot Methylomics
Guthrie cards (containing blood sample taken from every baby, to check for diseases) have recently been used to profile the methylome at birth, so that epigenetic variants present in patients can be identified before they are diagnosed with clinical disease. Because epigenome-wide association studies are being extensively performed to identify epigenetic variants associated to complex diseases, the methylome information provided by Guthrie cards may be valuable when trying to differentiate between disease-induced and disease-causal epigenetic variants. In this issue of Epigenetics, Ramagopalan and Rakyan review the promises and pitfalls of the use of Guthrie cards for disease research.
MyoD1 and the Activation of Muscle Enhancers
MyoD1 is a key regulator of skeletal muscle. Its role in transcriptional control at gene promoters is well known; nevertheless, little is known regarding the role of MyoD1 in the assembly of active enhancers. In this issue of Epigenetics, Blum and Dynlacht review novel data suggesting that MyoD1 mediates the assembly of active enhancers that augment the transcription of genes essential for muscle development and lineage specification.
Glioblastoma Epigenetics and Treatment
Glioblastoma multiforme (GBM) is the most common malignant adult brain tumor. Its recurrence has been linked to epigenetic mechanisms and pathways. Central to these pathways are epigenetic enzymes, which have recently emerged as possible new drug targets for multiple cancers. In this issue, Clarke et al. review GBM treatment, and provide a systems approach to identifying epigenetic drivers of GBM tumor progression. The authors also discuss advances in defining epigenetic mechanisms controlling GBM initiation and recurrence and the drug discovery considerations associated with targeting epigenetic enzymes for GBM treatment.
Placental HTR2A Methylation and Neurobehavioral Outcomes
The serotonin receptor, HTR2A, exhibits placental expression and function and can be controlled through DNA methylation. Paquette et al. studied the relationship between methylation of HTR2A in the placenta and neurodevelopmental outcomes in newborn infants. The authors found that HTR2A methylation was significantly higher in males and marginally higher in infants whose mothers reported tobacco use during pregnancy. These results suggest that methylation of the HTR2A gene can be biologically and environmentally modulated and is associated with key measures of neurodevelopment.
SNPs at CpGs and Methylation
The genetic determinants of DNA methylation patterns are poorly understood. Genetic variants at CpG sites (meSNPs) are likely to disrupt the substrate of methylation reactions and thus drastically change the methylation status at a single CpG site. However, it is unclear if meSNPs represent a major class of methylation-associated loci (meQTLs). Moreover, it is unclear if meSNPs modulate the methylation status of nearby CpG sites. In this issue, Zhi et al. investigated the impact of meSNPs on the methylation status of the CpG site harboring the SNP, as well as on surrounding CpG sites. The authors used high-resolution genotyping and epigenetic data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN), yielding a considerable amount of meSNPs with information on both genotype and methylation status. Their analysis suggests that meSNPs are behind a large portion of observed meQTL signals and play a crucial role in the biological process linking genetic variation to epigenetic changes.
Defining a Methylome Signature in Colorectal Cancer
CpG island methylator phenotype (CIMP) is one of the underlying mechanisms in colorectal cancer (CRC). Ashktorab et al. now aimed to define a methylome signature in CRC through a methylation microarray analysis and a compilation of promising CIMP markers from the literature. The authors identified 16 non-CIMP-panel genes for which they provide rationale for inclusion in a more comprehensive characterization of CIMP+ CRCs, contributing to better clinical management of CRC patients.
A Validation Analysis
The potential influence of underlying differences in relative leukocyte distributions in studies involving blood-based profiling of DNA methylation is well recognized and has prompted development of a set of statistical methods for inferring changes in the distribution of white blood cells using DNA methylation signatures. However, the extent to which this methodology can accurately predict cell-type proportions based on blood-derived DNA methylation data in a large-scale epigenome-wide association study has yet to be assessed. Koestler et al. now present further validation of this approach and highlight the promise of this technique for EWAS where DNA methylation is profiled using whole-blood genomic DNA.
CTCF and α-globin Gene Expression
Genomic loci composed of more than one gene are frequently subjected to differential gene expression. In this issue, Valdes-Quezada et al. studied the switching mechanisms responsible for the epigenetic silencing of the embryonic pi gene and the transcriptional activation of the adult alphaD and alphaA genes at the chicken α-globin genomic domain level. The authors propose that CTCF contributes to a specific chromatin configuration that is necessary for differential α-globin gene expression during development.
Radiation-Induced Changes in DNA Methylation
Therapeutic radiation results in a biological response to counter the subsequent DNA damage and genomic stress in order to avoid cell death. In this issue of Epigenetics, Antwih et al. analyzed DNA methylation changes at > 450,000 loci to determine a potential epigenetic response to ionizing radiation. The authors identified significantly differentially methylated genes that were enriched in gene ontology categories relating to cell cycle, DNA repair, and apoptosis pathways. These DNA methylation changes suggest an epigenetic role in the cellular response to radiation.
DNA Methylation and Nucleosome Occupancy at MAGEA11
MAGEA11 is a cancer germline (CG) antigen and androgen receptor co-activator. Previous in silico analysis revealed that MAGEA11 is frequently expressed in human cancers, is increased during tumor progression, and correlates with poor prognosis and survival. Now, James et al. show that in prostate and epithelial ovarian cancers, MAGEA11 expression was associated with promoter and global DNA hypomethylation, and with activation of other CG genes. MAGEA11 promoter activity was directly repressed by DNA methylation, and partially depended on Sp1. Importantly, DNA methylation regulated nucleosome occupancy specifically at the -1 positioned nucleosome of MAGEA11. Methylation of a single Ets site near the transcriptional start site (TSS) correlated with -1 nucleosome occupancy and, by itself, strongly repressed MAGEA11 promoter activity.
Epigenetic Control of an Adaptive Water Stress-Responsive Gene
Epigenetic events may have played important roles in the establishment of drought stress responses in plants. To investigate this issue, González et al. studied epigenetic marks in the tomato plant root (the crucial organ for sensing drought stress). The authors detected methylated epialleles of Asr2, a protein-coding gene widespread in the plant kingdom and thought to alleviate restricted water availability. They found that a brief exposure to simulated drought conditions caused the removal of methyl marks in the regulatory region of Asr2. Additionally, under normal conditions, both the regulatory and coding regions contained the typically repressive H3K9me2 mark, which was lost after 30 min of water deprivation. The authors speculate that rapidly acquired new Asr2 epialleles in somatic cells due to desiccation might be stable enough and heritable through the germ line across generations, efficiently contributing to constitutive, adaptive gene expression during the evolution of desiccation-tolerant populations or species.
E2f6-Mediated Repression of Meiotic Genes
The E2f6 transcriptional repressor is essential for the silencing of a group of meiosis-specific genes in somatic tissues. Here, Leseva et al. demonstrate that the inactivation of a group of E2f6 targeted genes, including Stag3 and Smc1β, first occurs at the transition from mouse embryonic stem cells to epiblast stem cells, which represent pre- and post-implantation stages, respectively. This process was accompanied by de novo methylation of their promoters. The authors present a vast amount of data suggesting a primary role of PRC2 in E2f6-mediated gene silencing of meiotic genes.
Submitted
7/23/13
Accepted
7/23/13