New research published in The FASEB Journal has reported that choline intake during pregnancy may have a significant effect on cortisol levels in offspring through epigenetic mechanisms. Choline, a methyl donor, may be able to alter fetal epigenetic marks, leading to significant functional changes in the child. Specifically, this study reports that high levels of choline intake as part of the maternal diet may be able to improve the stress response in children by lowering cortisol levels in the hypothalamic–pituitary–adrenal axis. Cortisol is thought to be important in a number of stress-related diseases in mental, metabolic and cardiovascular health, and lowering cortisol through choline supplementation could avoid disorders of these types.
For the main part of the investigation, the authors conducted a 12-week dose–response choline-feeding study in women who were in their third trimester of pregnancy. As an extension to this, the investigators examined the effect of maternal choline intake on the epigenetic state of cortisol-regulating genes, as well as their expression, in the placenta and cord venous blood. The women were divided into two groups: one consumed the control diet of 480 mg choline per day (the current dietary recommendation), while the other group consumed the treatment diet of 930 mg choline per day. To measure and analyze the blood levels of cortisol, the expression level of cortisol-regulating genes and the number of methyl groups attached to the DNA of these genes, maternal blood, cord blood and placental tissue were collected.
It was observed that the group receiving a higher intake of choline displayed increased placental promoter methylation of the cortisol-regulating genes, CRH and NR31C. This group also displayed lower placental CRH transcript abundance, lower cord blood leukocyte promoter methylation of CRH and NR31C, and 33% lower cord plasma cortisol. In addition to this, the researchers found that placental global DNA methylation and dimethylated histone H3 at lysine 9, as well as the expression of certain placental methyltransferases, were higher in the treatment group.
This research adds to a growing body of evidence that highlights the importance of maternal nutrition affecting the offspring through epigenetic mechanisms. Marie Caudill (Cornell University, NY, USA) senior author on the study, hopes that her group‘s research will have an impact in a clinical setting and improve guidelines concerning the diet of pregnant mothers: “We hope that our data will inform the development of choline intake recommendations for pregnant women that ensure optimal fetal development and reduce the risk of stress-related diseases throughout the life of the child.”
– Written by Jonathan Wilkinson
Source: Jiang X, Yan J, West AA et al. Maternal choline intake alters the epigenetic state of fetal cortisol-regulating genes in humans. FASEB J. 26(8), 3563–3574 (2012).
Research conducted by scientists at Oregon State University (OR, USA) has traced the actions of a known carcinogen in cooked meat to the complex biological effects on miRNA and cancer stem cells.
Traditionally, oncology studies have focused on changes in DNA sequence or mutations that allow for uncontrolled cell growth. However, the increasing interest in epigenetic studies, assessing how diet, environmental toxins and lifestyle affect the expression of genes, has led to various new insights into colorectal cancer.
Now, a recent study has used a systems biology approach to examine – for the first time – miRNAs altered in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, a heterocyclic amine carcinogen from cooked meat.
The results, published in Molecular Nutrition and Food Research, showed that among the most highly dysregulated miRNAs were those belonging to the let-7 family. Subsequent computational modeling and target validation identified c-Myc and miRNA-binding proteins Lin28A/Lin28B (Lin28) as key players, along with Sox2, Nanog and Oct-3/4. As such, these targets of altered miRNAs in colon cancers have been implicated in tumor recurrence and reduced patient survival.
Discussing the results, Mansi Parasramka, an author of the study said that: “We identified colon cancer-specific miRNA signatures and a panel of cancer signaling molecules which could be beneficial for diagnosis in patients and secondly, we investigated the chemoprotective effects of spinach in reducing colon cancer incidence.”
In parallel with these findings, the tumor-suppressive effects of dietary spinach given postinitiation correlated with elevated levels of let-7 family members and partial normalization of c-Myc, Sox2, Nanog, Oct-3/4, HmgA2, Dnmt3b and P53 expression. “We observed approximately 50% reduction in rat colon tumors in spinach-fed animals relative to regular diet, suggesting an inverse relation between spinach consumption and colorectal cancer risk,” Parasramka explained, “We observed that a spinach diet can alter cancer pathways by upregulating those factors that suppress tumor formation and simultaneously decrease the cancer-promoting molecules.”
Discussing future work, Parasramka said that: “At this point we are not completely sure if there is a particular component in spinach that is responsible for the outcome or if this is due the synergistic effect of whole food – spinach that has several micronutrients, chlorophyll, omega-3 fatty acids, carotenoids, antioxidants and several other phytonutrients. We are continuously screening for other cancer biomarkers.”
– Written by Ruth Williamson
Source: Parasramka MA, Dashwood WM, Wang R et al. MicroRNA profiling of carcinogen-induced rat colon tumors and the influence of dietary spinach. Mol. Nutr. Food Res. 56, 1259–1269 (2012).
An international group of genomic researchers have published findings suggesting that Guthrie cards may provide an archive of epigenetic information that could be analyzed to help understand disease and give an insight into the predicted health of a person. The authors write that one of the difficulties in the epigenomics of disease is distinguishing causal from consequential epigenetic variation. Currently, birth cohort studies are implemented to help identify the temporal origin of epigenetic variants by longitudinal analyses; however, this methodology is often expensive and time consuming. It appears that the information stored in Guthrie cards may provide a more efficient method of studying longitudinal analyses of in utero-derived DNA methylation.
Guthrie cards are used in healthcare to spot a newborn‘s blood onto filter paper, which can then be used for disease screening. Blood from the pricked heel of infants can be analyzed to determine the likelihood of the development of diseases such as cystic fibrosis, sickle-cell disorders and phenylketonuria. The investigators in this study, published in Genome Research, have shown that Guthrie cards provide a retrospective view of the epigenome at birth through longitudinal analysis. As many Guthrie cards are stored indefinitely by health authorities across the world, they may provide a unique and expansive amount of data about the epigenome at birth.
Vardham Rakyan (Barts and the London School of Medicine and Dentistry, London, UK) and colleagues first validated two methodologies for generating comprehensive DNA methylomes from the Guthrie cards. The genomic DNA was purified, and the methylomes were then analyzed to determine whether the archived DNA yielded high-quality methylation data compared with fresh samples. Using an integrated epigenomic analysis of the Guthrie cards and follow-up samples, the researchers identified interindividual DNA methylation that was present both at birth and 3 years later. These differences are most likely caused by environmental or random events in utero.
It appears that Guthrie cards, through genetic and epigenomic analysis, could provide a more complete picture of the genome at birth. The authors state that their findings suggest that disease-relevant epigenetic variation could be detected at birth, before the clinical aspects of the disease are triggered. Further to this, Guthrie card methylomics could become a powerful and cost-effective strategy for studying in detail interindividual epigenomic variation in a number of human diseases.
– Written by Jonathan Wilkinson
Source: Beyan H, Down T, Ramagopalan S et al. Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans. Genome Res. doi:10.1101/gr.134304.111 (2012) (Epub ahead of print).
Researchers at the University of California San Diego (CA, USA) have reported findings suggesting that DNA methylation may have a role in the development of rheumatoid arthritis (RA). It is claimed that methylation may alter genes associated with inflammation and joint damage leading to the disorder. Many genetic associations have been described in RA; however, twin studies have revealed that if one monozygotic twin develops the disorder, the other only has a 12–15% chance of also doing so. This led the researchers to consider epigenetic mechanisms as a potential factor in RA progression.
The authors stated that although the methylation of single genes has been reported in autoimmune diseases, no systemic analyses have been reported. Therefore, the authors performed a genome-wide evaluation of DNA methylation loci in fibroblast-like synoviocytes (FLS) isolated from the site of disease in RA. Genomic DNA was isolated from six RA and five osteoarthritis cell lines using the Illumina HumanMethylation450 chip. Methylation was confirmed by pyrosequencing and gene expression was determined by quantitative PCR.
When the DNA from the RA and osteoarthritis samples were compared, it was found that there were 1859 differently methylated loci between the two. Hypomethylated loci were observed in a number of genes thought to be involved in the RA, including CHI3L1, CASP1, STAT3, MAP3K5, MEFV and WISP3. This hypomethylation was associated with increased gene expression. In addition to this, hypermethylation was seen in the TGFBR2 and FOXO1 genes. Grouped analysis revealed 207 methylated genes with multiple differentially methylated loci, such as COL1A1, MEFV and TNF. The hypomethylation was observed in multiple pathways associated with cell migration, including processes such as focal adhesion, cell adhesion, transendothelial migration and extracellular matrix interactions.
This study revealed that FLS from RA patients are characterized by a DNA methylome signature that is unique from osteoarthritis and normal FLS. From these findings, the authors concluded that differentially methylated genes could alter FLS gene expression and be a contributing factor to the pathogenesis of RA. Research such as this highlights the important role of epigenetic mechanisms in the development of diseases such as inflammatory arthritis.
– Written by Jonathan Wilkinson
Source: Nakano K, Whitaker JW, Boyle DL, Wang W, Firestein GS. DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis. doi:10.1136/annrheumdis-2012–201526 (2012) (Epub ahead of print).