Newsweek: Transgenerational epigenetics is “the new Lamarckism”


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A recent article in Newsweek from science writer Sharon Begley reports on “the new Lamarckism,” citing studies from epigenetics researchers, including Emma Whitelaw. The article seems to be all about transgenerational epigenetics, but rather than ever use the word “epigenetics,” the favored term is “the new Lamarckism.” Link

But evidence for the new Lamarckism is strong enough to say the last word on inheritance and evolution has not been written.

My guess is that Begley was intent on building up controversy in her opening that seemed to be criticizing evolution during Darwin’s big 200/150 year. And in that regard, she piqued the interest of one of the most popular science bloggers, PZ Myers, who criticized the article in a post on his blog–sending tons of traffic to Newsweek.

It’s very cool stuff, but evolutionary biologists are about as shocked by this as they are by the idea that malnourished mothers have underweight babies. That environmental influences can have multi-generational effects, and that developmental programs can cue off of the history of the germ line, is not a new idea, especially among developmental biologists.

One of the problems with calling epigenetics “the new Lamarckism” is that it can have the connotation that the field is going the way of Lamarckism, or that geneticists are unable to account for (or are afraid of acknowledging) these strange phenomena. In truth, geneticists are aware of these phenomena, and are eager to see what mechanism is at play in the inheritance of these traits across generations–whether it be methylation, small RNAs, or a host of other possibilities.

But no one in science is crying over the fact that epigenetics is uncovering more details about how disease is acquired or traits inherited.

Epigenetics in Focus at Nature Reviews Genetics


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Following closely on the heels of the special issue of Cell on epigenetics, Nature Reviews Genetics today published its own focus issue on epigenetics (April 2007), with reviews from some of the most prominent experts in several sub-disciplines within epigenetics, including stem cell research, cancer epigenomics, and environmental epigenetics. The editors of the journal open the issue with a brief introduction:

The explosion of interest in epigenetics over the past few years has had an impact on many branches of genetic and genomic research. One of the hottest topics in the field of gene regulation relates to the role of epigenetic modifications in dictating the expression output of the genome. In genomics, the advent of technologies for the large-scale profiling of these marks has made the characterization of epigenomes a coveted goal. And chromosome biologists are increasingly learning how epigenetic modifications contribute to the structural packaging of the genetic material at various levels.

The cover of the issue, pictured below, is a cartoon sketchboard by the journal’s art editor, Patrick Morgan.

The issue is packed with five reviews on epigenetics topics of interest:

  • Environmental epigenomics and disease susceptibility by Jirtle RL and Skinner MK. Epigenetic modifications provide a possible link between the environment and disease-causing alterations in gene expression. Evidence from animal studies increasingly supports this theory, including recent findings of epigenetically mediated transgenerational alterations in phenotype that are caused by environmental exposure. Link
  • Epigenetic signatures of stem-cell identity by Spivakov M and Fisher AG. How do stem cells keep the genes that drive differentiation in a repressed state, while maintaining the ability to express them in the future? Increasing evidence indicates that distinctive epigenetic traits underlie this unique aspect of stem-cell biology. Link
  • Transposable elements and the epigenetic regulation of the genome by Slotkin RK and Martienssen R. Cells use a range of increasingly well understood epigenetic mechanisms to keep transposable elements under control. These silencing mechanisms have been co-opted during the course of evolution to contribute to key aspects of chromosome biology and gene regulation. Link
  • Cancer epigenomics: DNA methylomes and histone-modification maps by Esteller M. Recent technological advances allow epigenetic alterations in cancer to be studied across the whole genome. These approaches are being used to answer key outstanding questions about cancer biology, and to provide new avenues for diagnostics, prognostics and therapy. Link
  • The epigenetic regulation of mammalian telomeres by Blasco MA. Epigenetic modifications are key players in the regulation of fly and yeast telomeres, and recent studies indicate that the same applies in mammalian cells. These findings have implications for our understanding of the roles of telomeres in ageing and cancer. Link

The recent surge of coverage by high impact journals in the area of epigenetics likely reflects the major advances and discoveries made in recent years, and will hopefully provide renewed interest among scientists, funding bodies, and most importantly, the general public.

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.

Cell

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

Transgenerational Epigenetic Modification with Nutritional Supplementation


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Reader Israel Barrantes recently commented on what he considered to be the “most memorable epigenetic moment of the year” for 2006, which was a groundbreaking paper by Cropley et al. that appeared in Proceedings of the National Academy of Science in November (1). I couldn’t argue with that nomination, so I decided to write about the paper to kick off the week of Just Science.

The paper, titled “Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation,” uses a mutant mouse strain known as viable yellow agouti, or Avy. As shown previously, mice carrying the viable yellow agouti allele exhibit yellow fur, obesity, type II diabetes, and predisposition to tumors. Those that carry one Avy allele and one normal allele (referred to as Avy/a) exhibit varying degrees of the Avy phenotype, ranging from fully yellow and obese to lean and fully agouti. In previous studies, it has been shown that pregnant Avy females that receive a diet supplementation containing folate, choline, betaine, and vitamin B12 from two weeks prior to gestation to birth produce Avy offspring that are shifted toward the agouti phenotype. This shift was also highly correlated with an increase in cytosine methylation. In other words, nutritional supplementation during gestation seemed to cause an epigenetic alteration in phenotypes of offspring.

The picture below shows samples of the varying degrees of the yellow to agouti mice and their corresponding scores. The scores are used in this study as a quantitative way of determining the degree of tranmission of the Avy allele, comparing results when the mutant allele is contributed by the male (sire) or female (dam). The authors found that the previously mentioned shift to the agouti phenotype occurred only when the Avy allele was contributed by the sire, which provides evidence that the male germ line may play a role in transgenerational epigenetic alterations.

Agouti Mice

The authors then used this evidence of male-specific transmission of the Avy allele to propose that the altered phenotype could be passed to a subsequent generation without further diet supplementation. Further, they wanted to determine if diet supplementation was required throughout gestation to induce the epigenetic alteration. The authors proposed that supplementation was only critical during the period encompassing the point at which primordial germ cells differentiate and reset epigenetic marks. Therefore, the period of supplementation for pregnant a/a dams mated to Avy/a sires was set at E8.5 (embryonic day 8.5, or 8.5 days past conception) to E15.5. (Gestation in mice is about 21 days.) Interestingly, this midgestation exposure was very similar to the timepoint used in another study identifying a transgenerational epigenetic effect in mammals (2).

The authors found that when the F1 generation whose mothers received diet supplementation during gestation were mated, the F2 generation exhibited a similar shift in color score as the F1 generation. It is worth emphasizing that the F2 generation embryos were not directly exposed in utero to diet supplementation as the F1 generation embryos were, but the germ line of F2 animals was affected by the diet supplementation given to the previous generation.

This study was groundbreaking in that it provides the first direct evidence of a mechanism in a transgenerational, epigenetic alteration. However, it would be interesting to see if the shift to the agouti phenotype would continue into the F3 and F4 generations, as would be expected if the epigenetic germ line was permanently reprogrammed.

References:

1. Cropley JE, Suter CM, Beckman KB, Martin DIK.
2006. Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation. Proc Natl Acad Sci USA 103:17308-17312.
doi:10.1073/pnas.0607090103
2. Anway MD, Cupp AS, Uzumcu M, Skinner MK. 2005. Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility. Science 308:1466-1469.
doi:10.1126/science.1108190

Epigenetics Garners Fifth Spot in Discover’s Top Science Stories of 2006


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Discover Magazine has recognized several related discoveries in the field of epigenetics as the fifth top science story of 2006. The article details the research of Dr. Minoo Rassoulzadegan at the University of Nice:

    Minoo Rassoulzadegan’s mice are unruly. In blatant violation of the laws of genetics—described a century ago by famed monk-scientist Gregor Mendel—they inherit their parents’ coloring without inheriting the genes that cause it.
    Rassoulzadegan stumbled upon her rodent scofflaws after altering a gene in gray mice so that their feet and the tips of their tails turned white. The big surprise came in the next generation. Some offspring also had white spots, even though they didn’t inherit the mutated gene and so should have been all gray. When she looked for the cause, Rassoulzadegan found unusual amounts of RNA in the sperm of the mutant parents. She then injected RNA from the brains and sperm of those mice into ordinary gray mouse embryos. Many of the RNA-injected embryos likewise grew into white-tailed adults, regardless of the coloration written in their DNA.

The article also highlights the research of Dr. Vicki Chandler of the University of Arizona at Tucson and Dr. Michael Skinner of Washington State University. Link

Biomarkers In Focus At Environmental Health Perspectives


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The Focus article in the December issue of Environmental Health Perspective covers a term that should be very familiar to anyone following epigenetics: biomarker. While the term “biomarker” can be used to mean many different things, there are actually clear definitions for biomarkers that have been designated by scientists:

    In 1987, the National Research Council convened a committee to investigate how biomarkers were being developed and used in the environmental health sciences. The conclusions were documented in a seminal paper published in the October 1987 issue of EHP, which described the four basic biomarker groupings still in use today: exposure biomarkers (which include markers of external exposure and of internal dose); biomarkers of biologically effective dose; effect biomarkers (which include markers of health impairment or recognized disease, early disease precursors, or peripheral events that predict health impairment); and susceptibility biomarkers (which include intrinsic genetic or other characteristics or preexisting diseases that result in an increase in internal dose, biologically effective dose, or target tissue response).

EHP

One of the common ways that epigenetic researchers aim to identify a biomarker for a particular disease or phenotype is by measuring DNA methylation on specific gene promoters of interest — whether it be hypermethylation (an increase in DNA methylation) or hypomethylation (a decrease in DNA methylation). However, as the mechanism for linking a change in DNA methylation with disease susceptibility are not understood, there seems to be no clearly defined method for identifying an epigenetic biomarker using DNA methylation. Some researchers use a method that measures the percentage of methylated CG sites within a particular loci, while others examine specific CG sites and determine if any specific CG site’s methylation status is changed. These differing approaches, while both potentially useful in identifying changes in methylation pattern, may be a source of conflicting results in epigenetics research and could lead to a loss of confidence in using DNA methylation as a means of identifying clinically important biomarkers for disease. 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 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.

Link

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.

Declining Rates of Fertility and Epigenetics Research


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The Focus article in the November 2006 issue of Environmental Health Perspectives, entitled “Fertile Grounds for Inquiry: Environmental Effects on Human Reproduction,” is an interesting read for those interested in the reproductive effects of environmental toxicants and epigenetics.

    At a time when at least 80 million people worldwide are estimated to be affected by infertility, scientists are starting to look closely at how exposures to environmental substances may affect the ability of a couple to achieve a healthy pregnancy. Studies of wildlife and laboratory animals are helping to pin down how exposure to chemicals such as endocrine disruptors affects reproductive development, while human studies are looking at genetic effects, the effects of multicompound exposures, and the potential contribution of agricultural pesticides and persistent organic pollutants to problems such as low sperm counts and altered sex ratios. However, a thorough exploration of environmental effects on fertility will require the expertise of many different disciplines.
The article explores the issues of reducing fertility in both Europe and the United States, and offers commentary from researchers exploring the link between environmental toxicants and reduced fertility. It also introduces the field of epigenetics as an approach to linking the exposures of previous generations to the declining fertility of couples today, as was suggested by the 2005 Science paper “Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility.”

This paper came out of the lab of Dr. Michael Skinner, and two follow-up papers were recently published in the journal Endocrinology, which will be reviewed here in the near future. Link

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

An Epigenetic Factor in Increased Infant Mortality


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Epigenetics may play a role in the higher rates of infant mortality and low birth weight babies born to black women. The News and Advance reports this from Dr. Michael Lu of the UCLA School of Medicine and School of Public Health, as well as a co-principal investigator on a three-year, $15 million study on improving birth outcomes in Los Angeles.

    One hypothesis Lu cited is that during critical periods of development the fetus is impacted by the mother’s level of stress and the hormones it produces, which pass through the placenta. For critical developmental periods, that may affect organs or organ development in a way that “they don’t function optimally for an entire life course.”

    He said the new field of “epigenetics” takes the concept to the molecular level, as a “volume control for genes.” Gene expression can be turned up or down, switched on or off, by environmental exposure, “including pre-natal exposure.”

    With this theory, he said, identical genetic codes could play out very differently if one was developed under very high stress.

    Stress affects immune function, and some infections increase the possibility of pre-term labor, which leads to early delivery and low birth-weight babies.

Link

Hypermethylation of WRN Gene Promoter Linked to Human Cancer


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New research published in the Proceedings of the National Academy of Sciences suggests that increased methylation of the promoter sequence of the WRN gene is highly correlated with inactivation of the gene in human cancer cell lines.

    In this manuscript, we demonstrate that WRN undergoes CpG island promoter methylation-associated gene silencing in human cancer cells. The hypermethylation of the WRN promoter leads to its loss of expression and hypersensitivity to topoisomerase inhibitors and DNA-damaging agents. The epigenetic loss of WRN function can be rescued by the use of DNA-demethylating agents. Furthermore, the reintroduction of WRN into those transformed cell lines with WRN-deficiency due to hypermethylation provokes a reduction in colony formation and a decrease in growth of tumor xenografts, supporting the hypothesis that WRN has a tumor-suppressor role. The analysis of a large panel of human primary tumors (n = 630) shows that WRN CpG island hypermethylation is a common event in tumorigenesis. Most importantly, for colorectal cancer, the presence of aberrant methylation at the WRN promoter predicts improved survival in those patients treated with irinotecan, a topoisomerase inhibitor commonly used in this neoplasm. These findings underline the significance of WRN as a caretaker of our genome with tumor-suppressor activity and identify epigenetic silencing of WRN as a key step in cancer development that may have an important clinical influence on the treatment of these patients.
Link

The Epigenetics of Systemic Lupus Erythematosus (SLE)


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Systemic Lupus Erythematosus (SLE), which is the most common form of lupus, affects one out of every 285 Americans (Lupus Research Institute). Lupus is characterized as an autoimmune disorder, in which the immune system becomes hyperactive and produces antibodies that attack normal tissues and organs, such as the skin, brain, kidney, heart, lungs, and blood. Most people with lupus lapse between periods of illness, called flares, and periods of remission. Lupus can be a particularly debilitating disease, with symptoms that may include swollen and painful joints, severe fatigue, abnormal blood clotting, chest pain upon deep breathing, and seizures.

While these symptoms are treatable, and the majority of those who are affected by lupus are able to lead normal, healthy lives, the cause and development of SLE is poorly understood. The investigation of epigenetic mechanisms that may lead to development of lupus may be key to improved treatment options for those that suffer with this autoimmune inflammatory disease.

The June edition of the Journal of Immunology contains a brief review by Ballestar et al. on the research findings that point to an epigenetic “face” to the cause of SLE. For instance, drugs that demethylate T cells, such as 5-azacytidine, are used by researchers to induce lupus-like disease in mice. Additionally, demethylation of certain gene promoter and regulatory sequences contributes to aberrant overexpression of various genes. Both of these findings suggest that DNA methylation may play a role in the development of lupus.

Histone modifications may also play a role in the development of SLE. SLE Th cells show abnormal expression of certain gene products involved in regulation of the immune system, but these effects can be reversed with treatment using a histone deacetylase inhibitor. This finding provides evidence that histone modifications, another epigenetic alteration, could play a role in the development of lupus as well.

The authors of the paper make a strong recommendation for further research investigating the role that epigenetic alterations may play in developing lupus. “We truly believe,” the authors note, “that the future in the treatment of SLE depends greatly on the ability to revert epigenetic alterations…” Link