Retrotransposon Silencing by DNA Methylation Can Drive Mammalian Imprinting

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A new article was published today in PLoS Genetics concerning mammalian genomic imprinting — specifically, in the marsupial tammar wallaby (Macropus eugenii) and the egg-laying platypus (Ornithorhynchus anatinus):

Among mammals, only eutherians and marsupials are viviparous and have genomic imprinting that leads to parent-of-origin-specific differential gene expression. We used comparative analysis to investigate the origin of genomic imprinting in mammals. PEG10 (paternally expressed 10) is a retrotransposon-derived imprinted gene that has an essential role for the formation of the placenta of the mouse. Here, we show that an orthologue of PEG10 exists in another therian mammal, the marsupial tammar wallaby (Macropus eugenii), but not in a prototherian mammal, the egg-laying platypus (Ornithorhynchus anatinus), suggesting its close relationship to the origin of placentation in therian mammals. We have discovered a hitherto missing link of the imprinting mechanism between eutherians and marsupials because tammar PEG10 is the first example of a differentially methylated region (DMR) associated with genomic imprinting in marsupials. Surprisingly, the marsupial DMR was strictly limited to the 5′ region of PEG10, unlike the eutherian DMR, which covers the promoter regions of both PEG10 and the adjacent imprinted gene SGCE. These results not only demonstrate a common origin of the DMR-associated imprinting mechanism in therian mammals but provide the first demonstration that DMR-associated genomic imprinting in eutherians can originate from the repression of exogenous DNA sequences and/or retrotransposons by DNA methylation.

The full text is available for free to the public. Link

Cell Reviews Epigenetics and Chromatin Organization

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The journal Cell has released a special review issue, “Epigenetics and Chromatin Organization.” The issue contains 11 review articles, beginning with a review of one of the most exciting aspects of epigenetics: its effect on evolution.

According to classical evolutionary theory, phenotypic variation originates from random mutations that are independent of selective pressure. However, recent findings suggest that organisms have evolved mechanisms to influence the timing or genomic location of heritable variability. Hypervariable contingency loci and epigenetic switches increase the variability of specific phenotypes; error-prone DNA replicases produce bursts of variability in times of stress. Interestingly, these mechanisms seem to tune the variability of a given phenotype to match the variability of the acting selective pressure. Although these observations do not undermine Darwin’s theory, they suggest that selection and variability are less independent than once thought. Link

A nice summary of this review article is available at Gene Expression.


The other review articles include:

This special review issue from Cell is a clear indication of the role that epigenetics is playing in changing the scope and direction of scientific research in many different areas. My hope is that epigenetics will continue to inspire more articles in the press and will become well known among both those in science and the general public. Link

How I Found the Greally Lab

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The Greally lab was really easy to find. They linked to me. I have access to a nice stats package through my Web host that shows every referrer to Epigenetics News. So if any Web site links to any page of this site, I’ll eventually see it. Eventually, because there are now hundreds (if not thousands) of sites that link to Epigenetics News. And Dr. Greally, or presumably the person that updates their lab’s web page, decided to add a nice link to “Trevor Covert’s Epigenetics News site, a really valuable blog of all things current in the world of epigenetics.”

So, why should anyone care about the Greally lab? Well, as it turns out, they’re doing some fantastic epigenetics research. Based at the Albert Einstein College of Medicine in Bronx, New York, Dr. John M. Greally “has a long-standing interest in gene regulatory processes that extend over large regions of the genome and give rise to human diseases.”

Our major projects are centred on the discovery of DNA sequence characteristics that discriminate genes undergoing genomic imprinting, using these to find new imprinted genes that are candidates for causing human disease.

The technologies required for this research include innovative molecular assays and bioinformatics techniques. This combination provided the foundation for our recent new avenue of study into cytosine methylation patterns in large regions of the genome.

We use these techniques to learn the rules of normal epigenetic gene regulation through cytosine methylation, creating the foundation for understanding how it is disrupted in disease.

The disease-relevance of epigenetics is now being appreciated. The core dogma of medical genetics is that genes cause disease through mutations. However, this assumes that the gene is switched on appropriately to start with. In the field of cancer research in particular, it is now appreciated that inappropriate silencing of tumour-suppressor genes or activation of oncogenes through epigenetic dysregulation is a major contributor to neoplasia.

We study how the epigenome is altered in cancer, type 2 diabetes mellitus, aging, and as a response to diet and other influences. It is our belief that epigenetic dysregulation will prove to be a much more common cause of complex human diseases than DNA mutations.

I’d like to thank the Greally lab for their ongoing research because, without it, epigenetics would not be where it is today. Greally research articles Link

Shirley Tilghman Wins GSA Medal

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Princeton University President Shirley M. Tilghman has been awarded the Genetics Society of America Medal, which recognizes a scientist’s outstanding contributions to genetics over the past 15 years.

Tilghman was nominated for her pioneering work in epigenetics and imprinting, which has expanded the knowledge base about embryo development in mammals.

Tilghman published many papers characterizing the imprinted H19 and IGF2 genes, many of which can be seen here.

Jane Gitschier interviewed Shirley Tilghman last year in an article for PLoS Genetics. Link

Was 2006 a Good Year for Epigenetics? (Part II)

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In an earlier post, I began taking a look back at the year 2006 in epigenetics. With the last day of 2006 upon us, it seemed like a good time to complete the review of the year’s most memorable events (covered by Epigenetics News).

This is just a sample of what was covered in 2006. Look for even more coverage of everything epigenetics in 2007.

Was 2006 a Good Year for Epigenetics?

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Epigenetics, the study of heritable changes not involving changes in DNA sequence, saw a huge boost in public awareness in 2006. There were a number of high profile discoveries in the realm of epigenetics that were unveiled (or progressed) in 2006, which aid in increasing awareness of the field as a legitimate avenue to exciting advancements such as cancer treatment, early screening for cancer, the fetal basis of disease, and epigenetic inheritance in mammals.

  • The Journal of Epigenetics made its debut in 2006, which offers a new venue for topics such as DNA methylation, maternal and paternal imprinting, and histone modifications.
  • Discover Magazine featured a cover story on epigenetics, informing the larger public about the major advances that epigenetics is having on various areas of science and health.
  • Epigenomics, the company developing cancer screening tests based on DNA methylation-based biomarkers, made good progress during 2006, but encountered major setbacks during the latter half of the year. It will be interesting to see how Epigenomics fairs in 2007.
  • A new voice for epigenetics emerged in the form of a blog that aims to cover discoveries and advances in this sparsely covered field.

There were a number of other advances in epigenetics in 2006 that will be discussed in an upcoming post.

Update: Part 2 is now available.

Epigenetics in X-Linked Mental Retardation

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New research, currently in press from the international Journal of Cellular and Molecular Medicine, describes (speculative) evidence for an epigenetic link to human mental retardation.

    The search for the genetic defects in constitutional diseases has so far been restricted to direct methods for the identification of genetic mutations in the patients’ genome. Traditional methods such as karyotyping, FISH, mutation screening, positional cloning and CGH, have been complemented with newer methods including array-CGH and PCR-based approaches (MLPA, qPCR). These methods have revealed a high number of genetic or genomic aberrations that result in an altered expression or reduced functional activity of key proteins. For a significant percentage of patients with congenital disease however, the underlying cause has not been resolved strongly suggesting that yet other mechanisms could play important roles in their etiology. Alterations of the ‘native’ epigenetic imprint might constitute such a novel mechanism. Epigenetics, heritable changes that do not rely on the nucleotide sequence, has already been shown to play a determining role in embryonic development, X-inactivation, and cell differentiation in mammals. Recent progress in the development of techniques to study these processes on full genome scale has stimulated researchers to investigate the role of epigenetic modifications in cancer as well as in constitutional diseases. We will focus on mental impairment because of the growing evidence for the contribution of epigenetics in memory formation and cognition. Disturbance of the epigenetic profile due to direct alterations at genomic regions, or failure of the epigenetic machinery due to genetic mutations in one of its components, has been demonstrated in cognitive derangements in a number of neurological disorders now. It is therefore tempting to speculate that the cognitive deficit in a significant percentage of patients with unexplained mental retardation results from epigenetic modifications.

Imprinting Finding May Aid in Colorectal Cancer Screening

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Dr. Andrew Feinberg of the John Hopkins School of Medicine has announced at the 46th Annual Meeting of The American Society for Cell Biology that his lab has analyzed a common epigenetic alteration and found that mice with the loss of imprinting of IGF2 and a mutation in the Apc gene have a higher risk of developing colon cancer.

    Feinberg analyzed a common epigenetic alteration—found in 5–10 percent of the general population—that involves the loss of imprinting on an insulin-like growth factor gene called IGF2. Loss of imprinting of IGF2 has been associated statistically with individuals who have personal and familial histories of colorectal cancer. Turning to mice that modeled the loss of IGF2 imprinting, Feinberg found an increase in frequency of tumors in mice who also had mutations in a cancer-associated gene called Apc. In the mutant Apc mice, the loss of IGF2 imprinting seems to particularly affect the behavior of the adult stem cells that continually regenerate the colon in mice. This probably plays a role in the increased risk of colon cancer, says Feinberg.

This finding may help to develop better colon cancer screening tools. Link

Harvard Epidemiologist Seeks Postdoc in Epigenetics

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Dr. Karin Michels, an associate professor of Harvard Medical School and clinical epidemiologist of Brigham and Women’s Hospital, is seeking a postdoctoral research associate for her lab in Boston, MA.

    A postdoctoral position will be available at Brigham and Women’s Hospital, Harvard Medical School, to study gene imprinting and methylation starting in February or March 2007. The focus of our research is to identify environmental factors that predict loss of imprinting. A birth cohort is available to study epigenetic variation in newborns. We also examine imprinting pattern in human breast cancer. Candidates with strong background in molecular biology and epigenetics are encouraged to apply. Experience in human genome research and transcriptional gene regulation is particularly desirable.
Dr. Michels’ research interests focus on nutrition and women’s health (via Harvard School of Public Health):
    Her research ranges from early intrauterine nutrition of the fetus, breastfeeding and early life and adolescent diet to the role of adult diet on chronic disease risk, in particular, breast and other cancers. As diet is difficult to assess, Dr. Michels is studying the degree of measurement error associated with the different diet assessment methods. She is developing improved methods to analyze dietary data in epidemiologic studies. Dr. Michels is the Principal Investigator of a research grant from the National Institutes of Health to explore methods in nutritional epidemiology in the Nurses’ Health Study.

    Dr. Michels is also exploring the role of intrauterine and early life exposures in chronic diseases in adult life. Numerous studies have indicated that events in vitro may affect the risk of chronic disease in the offspring later in life. Dr. Michels is using several databases around the world to study this challenging hypothesis in more detail.

Dr. Karin Michels’ most recent publications. Link

Epigenetics May Hold Promise for Acute Lymphoblastic Leukemia

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A recent article in The New Zealand Herald reports on research investigating the cause of a common childhood cancer, acute lymphoblastic leukemia. Dr. Ian Morison, curator of the Imprinted Gene and Parent-of-origin Effects Database at Otago University, “is trying to pinpoint the exact period between conception and birth when leukaemic cells start to develop, and to better understand what genetic factors make that happen.” Dr. Morison is attempting to pin down why rates of leukemia have increased in recent years.

    “There seems to be something about modern life, but that doesn’t mean it’s cellphone towers – it could equally be the nutrition of the mum. It could be any one of a thousand factors we hadn’t thought of.”

    Epigenetics is a promising new area of interest.

    Traditionally, cancers were thought to be caused by gene mutations.

    “A mutation can affect just a single letter of DNA and disrupt a very important gene that puts brakes on a cell, controlling the cell’s growth,” said Dr Morison. “It’s like if a cable breaks on the handbrake of a car.”

    Otago’s Cancer Genetics Laboratory is looking at epigenetic changes, which modify cell function without mutation taking place.


New Research: Epigenetic Transgenerational Adult-Onset Disease

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New research from the laboratory of Dr. Michael Skinner at Washington State University shows that the endocrine disruptor vinclozolin, a fungicide used in agricultural crops such as grapes grown for the wine industry, can induce adult-onset diseases in the offspring of an exposed pregnant female rat such as prostate disease, kidney disease, immune system abnormalities, and tumor development that remain highly prevalent in four generations of offspring.

The December issue of the journal Endocrinology contains two articles related to the studies in the lab of Dr. Skinner, including “Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease” by Anway et. al and “Epigenetic Imprinting of the Male Germ-Line by Endocrine Disruptor Exposure During Gonadal Sex Determination” by Chang et. al. These research articles provide further insights into the phenomenon first described in the June 2005 issue of Science, “Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility.”

    The fetal basis of adult disease is poorly understood on a molecular level and cannot be solely attributed to genetic mutations or a single etiology. Embryonic exposure to environmental compounds has been shown to promote various disease states or lesions in the first generation (F1). The current study used the endocrine disruptor vinclozolin (antiandrogenic compound) in a transient embryonic exposure at the time of gonadal sex determination in rats. Adult animals from the F1 generation and all subsequent generations examined (F1–F4) developed a number of disease states or tissue abnormalities including prostate disease, kidney disease, immune system abnormalities, testis abnormalities, and tumor development (e.g. breast). In addition, a number of blood abnormalities developed including hypercholesterolemia. The incidence or prevalence of these transgenerational disease states was high and consistent across all generations (F1–F4) and, based on data from a previous study, appears to be due in part to epigenetic alterations in the male germ line. The observations demonstrate that an environmental compound, endocrine disruptor, can induce transgenerational disease states or abnormalities, and this suggests a potential epigenetic etiology and molecular basis of adult onset disease.
While one research article explores the disease prevalence across four generations of offspring after a single exposure to a pregnant female rat, the other characterizes specific genes and non-coding regions that exhibit altered methylation profiles in F2 and F3 generation males.
    Embryonic exposure to the endocrine disruptor vinclozolin at the time of gonadal sex determination was previously found to promote transgenerational disease states. The actions of vinclozolin appear to be due to epigenetic alterations in the male germline that are transmitted to subsequent generations. Analysis of the transgenerational epigenetic effects on the male germline (i.e. sperm) identified 25 candidate DNA sequences with altered methylation patterns in the vinclozolin generation sperm. These sequences were identified and mapped to specific genes and noncoding DNA regions. Bisulfite sequencing was used to confirm the altered methylation pattern of 15 of the candidate DNA sequences. Alterations in the epigenetic pattern (i.e. methylation) of these genes/DNA sequences were found in the F2 and F3 generation germline. Therefore, the reprogramming of the male germline involves the induction of new imprinted-like genes/DNA sequences that acquire an apparent permanent DNA methylation pattern that is passed at least through the paternal allele. The expression pattern of several of the genes during embryonic development were found to be altered in the vinclozolin F1 and F2 generation testis. A number of the imprinted-like genes/DNA sequences identified are associated with epigenetic linked diseases. In summary, an endocrine disruptor exposure during embryonic gonadal sex determination was found to promote an alteration in the epigenetic (i.e. induction of imprinted-like genes/DNA sequences) programming of the male germline, and this is associated with the development of transgenerational disease states.
This research has a number of potential implications:
  • Disease etiology and development mechanisms could involve this epigenetic transgenerational phenomenon and be a factor in disease development that is not currently not understood. What aspects of disease are due to DNA sequence mutations versus epigenetics involving chemical modification of the DNA?
  • Since this is an environmental effect that is multigenerational, it could explain why different sub-populations in different regions may develop different diseases.
  • This new phenomena may provide alternate approaches for disease diagnosis and therapy.
  • The influence of environmental toxicant exposures on disease development for offspring of exposed pregnant mothers needs to be further explored.
Disclosure: The publisher of Epigenetics News is a member of the laboratory involved in this research. No information related to this research that has not been published in a peer-reviewed scientific journal is contained in this article.

CpG Methylation System Revealed in Western Honey Bee

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Last week Science published several new reports on Apis mellifera, the honey bee, including a report from Wang et. al on the functional CpG methylation system in this newly sequenced genome. The methylation report has a number of key findings and implications for further research:

  • While the widely used genetics model Drosophila melanogaster shows only limited DNA methylation, the honey bee exhibits a fully functional CpG methylation system, including the identification of the deoxycytosine methyltransferase Dnmt2, as well as an ortholog for de novo methylation (AmDnmt3) and two orthologs for maintenance methylation (AmDnmt1a and AmDnmt1b).
  • Analysis thus far indicates that non-CpG methylation in the honey bee is either extremely rare or non-existent.
  • The authors propose that DNA methylation is widespread in insects, and thus Drosophila may be useful for understanding “unexplored evolutionary aspects of genome regulation.”
  • Since honey bees exhibit the underlying mechanisms that underlie imprinting, they could be used to test the kin-conflict theory.
  • All detected methylation in the honey bee was limited predominantly to coding regions.
  • The overall level of methylation in the honey bee is lower compared to vertebrates.
These findings could be important in providing a new understanding of how DNA methylation has evolved over time. Link

The Epigenetics of Lung Cancer

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Lung cancer and epigenetics have become inextricably linked. That’s the word from Dr. Annalese Semmler and colleagues from the The University of Queensland and The Prince Charles Hospital in Queensland, Australia in the journal Respirology.

In an invited review exploring the link between epigenetics and lung cancer, the Australian scientists do an admirable job of summarizing many of the discoveries made that offer new hope in lung cancer diagnostics and therapeutics.

For instance, both DNA hypomethylation (a loss of methylation) and DNA hypermethylation (an increase in methylation) have been linked to studies examining genes that are differentially methylated between normal and cancerous lung tissue. The genes that have been linked to altered methylation include those involved in cell cycle regulation, DNA repair, RAS signaling and invasion.

Epigenetics also provides an intriguing opportunity for the early detection of lung cancer. Various genes have been found to be differentially methylated in various body fluids that are potential biomarkers for the early detection of lung cancer, including sputum, bronchial lavage, and peripheral blood. These same biomarkers may also be useful in assessing the risk of a patient developing lung cancer, which could afford a chance for primary prevention (smoking cessation).

Demethylating drugs are also being investigated for their potential in the treatment of lung cancer. However, the authors stress that it will likely require new developments in demethylating agents to induce noticeable effects in lung cancer patients.

These and other links between epigenetic alterations and lung cancer provide researchers with a number of novel strategies for combating a cancer that affects millions around the world. Link

Epigenetic Map of Human Chromosomes 6, 20, and 22 Released

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Epigenomics AG and the Wellcome Trust Sanger Institute have released new data mapping the epigenetic state of human chromosomes 6, 20, and 22, providing the first tangible product of the Human Epigenome Project (HEP).

The analysis was completed using 43 human samples, and examined the methylation patterns in 12 different tissues. This was done in part to identify genes that are differentially methylated between DNA from various human tissues, which could affect gene expression.

Thus far, Epigenomics claims that the data is exciting because after examining over 2,500 different genomic loci, it found that “21 percent of all loci, or 17 percent of all genes on these chromosomes are differentially methylated in at least one of the examined tissue.” The company plans to publish details of these differentially methylated locations in the coming months.

The results of the whole chromosome analysis are patented. However, the methylation states of these three human chromosomes are available today through the Human Epigenome Project web site for use by non-commercial research groups. Link

Maternal vs. Paternal Imprinting: A Brief Review

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The July edition of Nature Reviews Genetics contains a brief article summarizing recent research into the question, “Do mothers and fathers imprint differently?”

    Two imprinting mechanisms have been described to date: one involves an imprinting control region (ICR) at the well-studied H19/Igf2 locus. On the maternal chromosome the ICR acts as an insulator to inhibit expression of Igf2, whereas DNA methylation of the ICR on the paternal allele spreads to and silences the H19 gene. The other mechanism involves an ICR that acts as a promoter for a paternally expressed non-coding RNA, first described at the Igf2r locus by Denise Barlow and colleagues. Kcnq1ot1 is the second example of a non-coding RNA with a direct role in the silencing of imprinted genes. The fact that the activity of the ICR in the first mechanism occurs on the maternal chromosome whereas in the second, described by Tilghman and colleagues, the activity applies to the paternal chromosome raises the possibility that the two mechanisms are gender-specific. Understanding how other clusters of imprinted genes are silenced should verify this interesting possibility.
The research paper from Mancini-DiNardo, D. et al. entitled “Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes” appeared in volume 20 of Genes Development. (The research highlights from NRG are free to the public, registration required.) Link