Researchers aim to determine whether environmental factors could influence CpG methylation that may increase the risk of developing colorectal cancer.
Carcinogenesis is a focus of many research projects, including those concerning epigenetics. A recent study conducted by Nigel Belshaw (Institute of Food Research, Norwich, UK) and colleagues looked at how several factors could influence the methylation status of genes expressed in rectal cells. The group noted that abnormal CpG island (CGI) methylation was present in various genes expressed by colon cells. In addition, this methylation may impact the dysregulation of signaling pathways that are characteristic of some cancers.
The cross-sectional study that was recently published in Aging Cell, analyzed the significance of numerous factors on CGI methylation. This was achieved by studying rectal biopsies from individuals free from colorectal disease. The group explained to Epigenomics that they obtained information concerning “age, sex, measures of body size, blood cell counts and status of some nutrients.” They proceeded to use quantitative DNA methylation analysis and multivariate modeling to identify potential relationships between these factors and CGI methylation.
The researchers noted that age appeared to predict CGI methylation in nine of the 11 genes studied. Furthermore, CGI methylation seemed higher in males, and methylation in males and females was differentially affected by several factors. Belshaw told Epigenomics that these findings are “consistent with age being the biggest risk factor for colorectal cancer,” in addition to being male.
The group also noted that associations were noticed for selenium, vitamin D and white blood cell counts, which were negatively correlated with methylation. In addition, folate status, body size and monocyte counts demonstrated a positive correlation with methylation. When obtaining these results, the investigators revealed that they faced challenges concerning “the frequent subtle effects for some of the factors identified to influence gene-specific methylation that could only be detected using a sensitive quantitative method for methylation analysis and sophisticated statistical modeling techniques.”
The authors of the study concluded that the amount of CGI methylation observed in rectal cells appears to be influenced by gender, folate availability, selenium, vitamin D and, potentially, by factors associated with inflammation. The group believes these results “increase our understanding of how diet, and perhaps other lifestyle factors, influence the aging process with implications for disease risk.” The results of this study indicate that research into the relationship between folate intake, DNA methylation and carcinogenesis is necessary to determine the optimal dietary intake of folate.
Source: Tapp HS, Commane DM, Bradburn DM et al. Nutritional factors and gender influence age-related DNA methylation in the human rectal mucosa. Aging Cell doi:10.1111/acel.12030 (2012) (Epub ahead of print).
Study aims to elucidate the processes of demethylation and transgenerational epigenetic inheritance in primordial germ cells.
It appears that genome-wide DNA methylation reprogramming takes place in the primordial germ cells and preimplantation embryos of mice. However, there remains a lack of understanding regarding the specific dynamics or results of this process. To attempt to elucidate this, Wolf Reik and coworkers (The Babraham Institute, Cambridge, UK) studied demethylation and transgenerational epigenetic inheritance in mice. This seems especially important owing to the interest surrounding DNA methylation – is the majority active, passive or both?
Molecular Cell recently published this study, whereby the investigators employed whole-genome bisulfite sequencing and RNA-seq in epiblasts and primordial germ cells. The group noted that a global loss of methylation appeared to occur during primordial germ cell expansion and migration. This seemed to be a result of passive demethylation, which occurs when methylation is not maintained during cell replication. Despite this, the sequences carrying long-term epigenetic memory are only demethylated once the primordial germ cells enter the gonads.
This study also looked at the topic of inherited epigenetic information. As Reik explained to Epigenomics, “most epigenetic information is erased, but not all of it, so it is interesting to look in detail at what is left and passed from generation to generation.” The interest surrounding the existence and role of transgenerational epigenetic inheritance may be heightened by this study as “some sequences, although not many, retain information that could show potential transinheritance.” As a result, it is felt that developments in this field could allow investigators to look “more deeply to determine how the epigenetic information that is not erased and gets transmitted to the next generation could influence inheritance and, subsequently, disease susceptibility in humans.” Furthermore, the results could provide additional mechanistic knowledge to develop future insight into how reprogramming works and put experimental programming into practice; for example, to generate better induced pluripotent stem cells.
The results from this research were not obtained without their challenges. Reik told Epigenomics that a significant technical challenge was that one could only harbor hundreds or thousands of germ cells at one time. Therefore, there seems a “need to improve existing techniques with high-throughput sequencing.” In this study, the investigators used fluorescent markers and bioinformatics to try and overcome such challenges.
The observation that the “transcriptional profile of primordial germ cells is tightly controlled despite global hypomethylation, with transient expression of the pluripotency network” could suggest that epigenetic reprogramming and pluripotency are inextricably associated. Furthermore, the group claim the results could help develop our knowledge of the epigenetic ground state of pluripotency in the germline. It is hopeful that understanding the epigenetics behind germline pluripotency could impact future research. Based on the findings of this study, the investigators believe that the next logical step includes analyzing the earliest embryonic cells to determine what instructs them to “switch on or off epigenetic machinery that erases methylation, how it is brought about and how the process can be manipulated.”
Source: Seisenberger S, Andrews S, Krueger F et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48(6), 849–862 (2012).
Circadian rhythms have been a subject of interest for a number of years. There have yet to be any systematic investigations concerning the potential roles of epigenetic modifications in transcript oscillations. However, a study conducted by Joseph Ecker (Salk Institute for Biological Studies, CA, USA) and colleagues has analyzed circadian transcript oscillations in the livers of adult mice. Research in this area may be of interest as it could develop the understanding of metabolism, circadian rhythms and epigenetic modifications that occur in metabolic homeostasis.
The research, recently published in Cell Metabolism, involved a 24-h, genome-wide integrative study to determine whether there is a link between “the dynamic hepatic transcriptome and its epigenome in adult mouse livers.” The investigators employed deep sequencing to identify temporal changes in the levels of miRNAs, strand-specific RNA, certain histone modifications and cytosine DNA methylation.
In the published study, the investigators claim to have discovered circadian oscillations in mRNAs, several antisense RNA, miRNA and lincRNA transcripts. Furthermore, the group found that despite no notable changes in promoter DNA methylation being related to transcript oscillations, there did appear to be a correlation with histone modifications in enhancers, promoters or gene bodies. It is believed that the detection of oscillations in histone modifications at enhancers allows “establishment of functional transcript–enhancer associations.”
The research indicates that there is oscillating expression of an antisense transcript of the gene encoding Per2. In addition, oscillating transcripts coupled with histone modifications led the group to suggest that there is a “temporal relationship between enhancers, genes and transcripts on a genome-wide scale in a mammalian liver.” Such results could subsequently aid further research into understanding the associations and dynamics of circadian clocks, metabolism and chromatin modifications in metabolism.
Source: Vollmers C, Schmitz R, Nathanson J, Yeo G, Ecker J, Panda S. Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. Cell Metab.16(6), 833–845 (2012).
Recent study demonstrates the possible mechanisms that cause gene activation and deregulation in carcinogenesis.
Many cancer epigenetics studies have noted that epigenetic gene deregulation in the disease often occurs via promoter hypermethylation of tumor-associated genes, in addition to chromatin repression. Despite these observations, there remains a lack of knowledge surrounding the mechanism behind epigenetic-based gene activation in the process of carcinogenesis. However, Susan Clark (Garvan Institute of Medical Research, New South Wales, Australia) and colleagues have sought to help bridge this gap in our knowledge in a recent study published in Cancer Cell.
The investigators analyzed prostate cancer cells using gene-expression profiling, in addition to genome-wide sequencing data, in order to discover epigenetically activated areas of the genome. The analyses resulted in the group determining a potential mechanism of “domain gene deregulation through coordinated, long-range epigenetic activation” of segments that are approximately 1 Mb long and contain specific oncogenes, cancer-related genetic biomarkers and miRNAs.
In the published research, the investigators claimed that additional active chromatin marks and fewer repressive marks are characteristic of gene promoters in long-range epigenetic activation domains. Furthermore, despite promoter hypomethylation only being occasional, the group demonstrated that a significant level of DNA hypermethylation of CpG islands could be observed and associated with cancer-specific gene activation.
This investigation into the mechanisms underlying epigenetic-related gene activation in tumorigenesis may encourage future research that could further develop our knowledge in this field. In addition, the authors of the study feel that the results could “have wide ramifications for cancer diagnosis, progression and epigenetic-based gene therapies.”
Source: Bert SA, Robinson MD, Strbenac D et al. Regional activation of the cancer genome by long-range epigenetic remodeling. Cancer Cell doi:10.1016/j.ccr.2012.11.006 (2012) (Epub ahead of print).
A study has revealed that hypomethylation of the IL17RC promoter may be associated with age-related macular degeneration.
The most common cause of blindness among the elderly population is age-related macular degeneration (AMD). Several studies into the disorder have noted that SNPs in numerous genes are linked with AMD. However, research performed by Robert Nussenblatt (NIH, MD, USA) and colleagues aimed to identify epigenetic processes of regulation that may also be significant factors in the etiology of AMD. Specifically, the group focused their research on the methylation of the IL17RC gene.
The research, which was published in a recent issue of Cell Reports, was focused on determining whether studying pairs of twins could result in the detection of methylation changes. The group chose to do twin studies as they have been shown to “provide a means of dissecting the genetic and environmental components of disease.” In the study, the group analyzed genome-wide differences in the DNA methylation patterns between both monozygotic and dizygotic twins with discordant AMD. They investigated the methylation changes further by examining the IL17RC promoter in both twins with discordant AMD.
The investigators noted a decreased level of DNA methylation on the IL17RC promoter, leading to increased gene activity. This rise in gene activity led to the production of more IL17RC proteins, which are known to be involved in the immune response to various infections. These proteins and the corresponding mRNA were detected in peripheral blood, affected retinas and choroids, and potentially led to “cellular dysfunction and disease.” As the DNA in the affected individuals remained normal, but the gene expression was altered, it seems viable to assume that the findings of this study are epigenetic.
The results of this experiment led to the investigators concluding that the “DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis.” In a press release from the National Eye Institute (MD, USA), it was revealed that in the future, the investigators plan to determine the environmental factors that may be responsible for the epigenetic regulation and how therapies could reverse the chronic inflammation associated with AMD.
Sources: Wei L, Liu B, Tuo J et al. Hypomethylation of the IL17RC promoter associates with age-related macular degeneration. Cell Rep. 2(5), 1151–1158 (2012); National Eye Institute Press Release 2012: www.nei.nih.gov/news/pressreleases/112712.asp
– All stories written by Jonathan Wilkinson