An expression profiling screen of genes responding to paternal diet suggests that the diet of the father can affect the transgenerational inheritance of environmental information.
The research, which was carried out at the University of Massachusetts Medical School, MA, USA, and is featured in the journal Cell, marks a progression from the belief that only the maternal diet affects offspring and could help identify individuals at high risk of illness such as heart disease and diabetes.
Commenting on the importance of the study, lead researcher Dr Oliver Rando stated: “Knowing what your parents were doing before you were conceived is turning out to be important in determining what disease risk factors you may be carrying. A major and underappreciated aspect of what is transmitted from parent to child is ancestral environment”.
The study comprised two groups of male mice – one received a standard diet, and the other a low-protein diet. The low-protein group of mice was found to have offspring with an elevated hepatic expression of many genes involved in lipid and cholesterol biosynthesis – indicating an increased risk of heart disease. In addition, the epigenomic profiling of offspring livers revealed a modest (∼20%) alteration in cytosine methylation dependant on paternal diet, including an increased methylation of the lipid regulator Ppara enhancer.
Viewing the results from an evolutionary standpoint, Dr Hans Hofmann, associate professor of integrative biology at the University of Texas at Austin, TX, USA, and a coauthor of the study remarked: “It has increasingly become clear in recent years that mothers can endow their offspring with information about the environment, for instance, via early experience and maternal factors, and thus make them possibly better adapted to environmental change. Our results show that offspring can inherit such acquired characters even from a parent they have never directly interacted with, which provides a novel mechanism through which natural selection could act in the course of evolution”.
However, it is still unclear how the differences in methylation get transmitted to the offspring: “We don‘t know why these genes are being reprogrammed or how, precisely, that information is being passed down to the next generation. It‘s consistent with the idea that when parents go hungry, it‘s best for offspring to hoard calories, however, it‘s not clear if these changes are advantageous in the context of a low-protein diet”, remarked Dr Rando.
This marks a progression from previous studies which were unable to rule out socioeconomic factors. Dr Rando concluded: “Our study begins to rule out the possibility that social and economic factors, or differences in the DNA sequence, may be contributing to what we‘re seeing. It strongly implicates epigenetic inheritance as a contributing factor to changes in gene function”.
Source: Carone BR, Fauquier L, Habib N et al.: Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143(7), 1084–1096 (2010).
Scientists in the UK are the first to discover that homocysteine (a critical metabolite of folic acid) levels in fetal cord blood are linked to gene-specific methylation patterns and birthweight in newborns. This state-of-the-art epigenetic study was performed by scientists at Keele (Staffordshire, UK) and Nottingham Universities (Nottingham, UK) together with doctors at University Hospital of North Staffordshire (Stoke-on-Trent, UK) and Derby Children‘s Hospital (Derby, UK) and was recently published in the journal, Epigenetics. By investigating the specific methylation patterns in more detail, the researchers may be able to identify regions essential in fetal development.
The microarray technique employed by researchers simultaneously examined methylation at 27,578 sites in the DNA. Lead researcher William Farrell, Professor of Human Genomics, Institute for Science and Technology in Medicine at the University of Keele, remarked: “It has been known for many years that folic acid supplementation is essential for women during pregnancy to reduce the risk of neural tube defects and low birthweight delivery. However, we had little idea as to how this worked. This study is the first to suggest that methylation of particular genes in the baby‘s DNA may be the key to unlocking the secret of the action of folic acid”.
Commenting on the implications of the findings, Dr Farrell stated: “Now, we have identified which genes might be the link between folic acid and birthweight, we have opened the door to research that may allow doctors to predict the likelihood of low birthweight with greater certainty. Furthermore, it sheds light on the under lying causes of low-birthweight and offers the potential to intervene earlier to prevent poor pregnancy outcomes such as premature delivery and pregnancy loss”.
Source: Fryer AA, Emes RD, Ismail K et al.: Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans. Epigenetics 6(1), 86–94 (2011).
A group of scientists at the University of Hong Kong (Hong Kong, China) led by Dr Hongping Xia have coined miR-200a ‘a new gatekeeper of cancer metastasis‘. Through overexpression and knockdown experiments on nasopharyngeal carcinoma (NPC) cells, the short RNA molecule was identified as a regulator of the epithelial–mesenchymal transition (EMT) via ZEB2 and β-catenin signaling, a transition believed to mark the initiation of metastasis, as well as a regulator of stem-like transition.
The generation of cancer stem cells from EMT is an emerging concept which has already attracted great interest, yet the means by which this putative tumor-initiating process proceeds remain largely elusive.
Following on from studies on the involvement of histone and DNA methylation in EMT, the Hong Kong researchers concentrated on the role of miR-200a in the creation of cancer stem cell in NPCs. The knockdown of miR-200a in NPCs led to not just an EMT (with the transition of epithelium-like CNE-1 cells to the mesenchymal phenotype), but also a stem-like transition which the authors assigned the term ‘epithelial–mesenchymal to stem-like transition‘.
In addition, miR-200a overexpression reverts mesenchymal-like cells (C666–1 cells) back to an epithelial state, and suppresses stem-like traits including CD133+ side population, sphere formation capacity, in vivo tumorigenicity in nude mice and stem cell marker expression.
The molecular mechanism behind EMT was found to be the targeting of ZEB1 by miR-200a, whereas the stem-like transition was regulated differentially and specifically by β-catenin signaling. Post miR-200a knockdown, CTNNB1 re-expression brings back stem-like phenotypes that were lost.
Source: Hongping X, Cheung WKC, Sze J et al.: miR-200a regulates epithelial–mesenchymal to stem-like transition via ZEB2 and β-catenin signaling. J. Biol. Chem. 285(47), 36995–37004 (2010).
A collaborative genome-wide study between Duke University, NC, USA, Kyoto University, Japan, and the National Hospital Organization Kyoto Medical Center, Japan, provides new evidence for the accumulation of age-related epigenetic modifications which allow the cancerous growth of cells. The study, which aimed to elucidate the biological and clinical relevance of DNA methylation in ovarian cancer – a leading cause of death among gynecologic malignancies, highlights the TGF-β signaling pathway as having genes under the control of DNA methylation in tumor cells. The study is published in the journal, Genome Research.
In order to identify the genes silenced by DNA methylation and potentially involved in the disease, the international team of researchers performed expression microarray analysis of 39 cell lines and 17 primary culture specimens grown in the presence or absence of DNA methyltransferase inhibitors. The induction of expression and standard deviation among untreated samples then allowed researchers to identify 378 candidate methylated genes. From this group, all 43 of the predicted genes exhibited methylation in ovarian cancer.
Commenting on the findings of the study, senior author Dr Susan Murphy, assistant professor in the Division of Gynecologic Oncology in Duke OB-GYN and in the Department of Pathology stated: “While we hoped to identify a substantial group of candidate methylated genes, we did not anticipate that we would find methylation-mediated deregulation of many genes involved in a specific functional pathway, the TGF-β pathway”.
Upon treatment of the tumor cells with methylation inhibitors, the TGF-β pathway, which ensures proper cell growth, cell differentiation and apoptosis, exhibited increased activity. This is the first time that the TGF-β pathway function has been shown to be regulated via methylation. “This is only one piece of a larger puzzle about the biology of ovarian cancer, but we can say that DNA methylation does have an influence on suppressing TGF-β pathway signaling, which contributes to ovarian cancer,” commented Dr Murphy.
In addition, a cluster of genes that strongly correlated with TGF-β pathway activity in specimens from older women suggests that age-related epigenetic changes can accumulate and may contribute to cancer.
Dr Murphy went on to speculate: “Knowing the identity of these genes provides for the ability to carry out focused studies to understand their specific role in ovarian cancer, and may present opportunities for targeted therapeutic interventions”.
Different approaches may have to be taken for different patients: “Some women with ovarian cancer have lower expression of these tumor-suppressing genes and may be amenable to epigenetic therapies that lead to gene reactivation – with the caveat that at this point we can‘t epigenetically reactivate just one gene or a specific group of genes”, Dr Murphy explained. “Another group of women with ovarian cancer have higher expression of these genes, suggesting it may be possible to specifically inhibit particular components in this pathway to stop tumor development or progression”.
Source: Matsumura N, Huang Z, Mori S et al.: Epigenetic suppression of the TGF-β pathway revealed by transcriptome profiling in ovarian cancer. Genome Res. 21(1), 74–82 (2011).