Welcome to the Podiatry Arena forums, for communication between foot health professionals about podiatry and related topics.
You are currently viewing our podiatry forum as a guest which gives you limited access to view all podiatry discussions and access our other features. By joining our free global community of Podiatrists and other interested foot health care professionals you will have access to post podiatry topics (answer and ask questions), communicate privately with other members (PM), upload content, view attachments, receive a weekly email update of new discussions, earn CPD points and access many other special features. Registered users do not get displayed the advertisments in posted messages. Registration is fast, simple and absolutely free so please, join our global Podiatry community today!
If you have any problems with the registration process or your account login, please contact contact us.
The incidence of diabetes mellitus, a chronic metabolic disease associated with both predisposing genetic and environmental factors, is increasing globally. As a result, it is expected that there will also be an increasing incidence of diabetic complications which arise as a result of poor glycemic control. Complications include cardiovascular diseases, nephropathy, retinopathy and diabetic foot ulcers. The findings of several major clinical trials have identified that diabetic complications may arise even after many years of proper glycemic control. This has led to the concept of persistent epigenetic changes. Various epigenetic mechanisms have been identified as important contributors to the pathogenesis of diabetes and diabetic complications. The aim of this review is to provide an overview of the pathobiology of type 2 diabetes with an emphasis on complications, particularly diabetic foot ulcers. An overview of epigenetic mechanisms is provided and the focus is on the emerging evidence for aberrant epigenetic mechanisms in diabetic foot ulcers.
Press Release: Epigenetics alters genes in rheumatoid arthritis
Quote:
It's not just our DNA that makes us susceptible to disease and influences its impact and outcome. Scientists are beginning to realize more and more that important changes in genes that are unrelated to changes in the DNA sequence itself – a field of study known as epigenetics – are equally influential.
A research team at the University of California, San Diego – led by Gary S. Firestein, professor in the Division of Rheumatology, Allergy and Immunology at UC San Diego School of Medicine – investigated a mechanism usually implicated in cancer and in fetal development, called DNA methylation, in the progression of rheumatoid arthritis (RA). They found that epigenetic changes due to methylation play a key role in altering genes that could potentially contribute to inflammation and joint damage. Their study is currently published in the online edition of the Annals of the Rheumatic Diseases.
"Genomics has rapidly advanced our understanding of susceptibility and severity of rheumatoid arthritis," said Firestein. "While many genetic associations have been described in this disease, we also know that if one identical twin develops RA that the other twin only has a 12 to 15 percent chance of also getting the disease. This suggests that other factors are at play – epigenetic influences."
DNA methylation is one example of epigenetic change, in which a strand of DNA is modified after it is duplicated by adding a methyl to any cytosine molecule (C) – one of the 4 main bases of DNA. This is one of the methods used to regulate gene expression, and is often abnormal in cancers and plays a role in organ development.
While DNA methylation of individual genes has been explored in autoimmune diseases, this study represents a genome-wide evaluation of the process in fibroblast-like synoviocytes (FLS), isolated from the site of the disease in RA. FLS are cells that interact with the immune cells in RA, an inflammatory disease in the joints that damages cartilage, bone and soft tissues of the joint.
In this study, scientists isolated and evaluated genomic DNA from 28 cell lines. They looked at DNA methylation patterns in RA FLS and compared them with FLS derived from normal individuals or patients with non-inflammatory joint disease. The data showed that the FLS in RA display a DNA methylome signature that distinguishes them from osteoarthritis and normal FLS. These FLS possess differentially methylated (DM) genes that are critical to cell trafficking, inflammation and cell–extracellular matrix interactions.
"We found that hypomethylation of individual genes was associated with increased gene expression and occurred in multiple pathways critical to inflammatory responses," said Firestein, adding that this led to their conclusion: Differentially methylated genes can alter FLS gene expression and contribute to the pathogenesis of RA.
Metabolic Memory and Chronic Diabetes Complications: Potential Role for Epigenetic Mechanisms.
Intine RV, Sarras MP Jr. Curr Diab Rep. 2012 Jul 4
Quote:
Recent estimates indicate that diabetes mellitus currently affects more than 10 % of the world's population. Evidence from both the laboratory and large scale clinical trials has revealed that prolonged hyperglycemia induces chronic complications which persist and progress unimpeded even when glycemic control is pharmaceutically achieved via the phenomenon of metabolic memory. The epigenome is comprised of all chromatin modifications including post translational histone modification, expression control via miRNAs and the methylation of cytosine within DNA. Modifications of these epigenetic marks not only allow cells and organisms to quickly respond to changing environmental stimuli but also confer the ability of the cell to "memorize" these encounters. As such, these processes have gained much attention as potential molecular mechanisms underlying metabolic memory and chronic diabetic complications. Here we present a review of the very recent literature published pertaining to this subject.
Bob, I actually find this whole topic very interesting. I had to do some searching to see what you meant by Lamarck. I assume you meant this:
__________________ Craig Payne
__________________________________________________ ___________________________________ Follow me on Twitter | Run Junkie God put me on this earth to accomplish a certain number of things - right now I am so far behind, I will never die.
When I was a student of evolutionary biology (1985), the white-anting of Lamark was beginning to turn. No one is suggesting the inheritance of acquired characteristics is his sense, typified by the Blacksmith who got big and strong, so that his future kids would be also big and strong. Waddington in the 50's suggested that we lived on an "epigenetic lanscape" where we were simply a mixture of our genetics and out environment (he coined the term epigenetics); years later genetic assimilation was put forward, and like most astounding ideas, was originally laughed out of town (sound familiar?). Later, a UK biologist, Ted Steele, that eventually finished up at Wollongong, reconned he could measure, with multivariate stats (which is why it caught my attention) diploid/haploid transition. THAT IS, the crossing of Weisman's barrier. Genetic assimilation is now accepted, and the last time I talked about it on this arena, I used terms like "though an exact mechanism has yet to be identified". Through talking to brains far greater than mine at last years Human Biology conference, I gather that at the molecular level, this is no longer true, they are identified. I got into this stuff 20 years ago to study squatting facets on the homo talus; it is no less and no more valid there than anywhere else. However, In a recent study of ours into "cold adaptations" in eskimos from Cagamill Island in Alaska, and Pre-contact American Indian from South Dakota, we may well be look at the same thing: within a very few generations (far too small for natural selection, I think), we see a reduction in the surface area touching the ground, and thus able to loose heat through conduction. All my specimens for this study came from the Smith - I cannot speak to highly of them - they even let my wife play in Apollo 11 while I worked! Rob
__________________
Honorary Research Associate, Institute for Human Evolution, University of Witwatersrand
Adjunct Associate Professor (Human and Comparative Anatomy), University of Western Sydney
Fellow of The Centre For Human Biology, The University of Western Australia
"Please God, deliver me whole from Creationists......."
Press Release: Epigenetic Cause of Osteoarthritis Identified
New research in the FASEB Journal suggests that DNA methylation is responsible for switching on and off a gene that produces the MMP13 enzyme that is known to be important in the destruction of cartilage
Quote:
In what could be a breakthrough in the practical application of epigenetic science, U.K. scientists used human tissue samples to discover that those with osteoarthritis have a signature epigenetic change (DNA methylation) responsible for switching on and off a gene that produces a destructive enzyme called MMP13. This enzyme is known to play a role in the destruction of joint cartilage, making MMP13 and the epigenetic changes that lead to its increased levels, prime targets for osteoarthritis drug development. In addition to offering a new epigenetic path toward a cure for osteoarthritis, this research also helps show how epigenetic changes play a role in diseases outside of cancer. This finding was recently published online in the FASEB Journal.
"As the population gets older, osteoarthritis presents increasing social and economic problems," said David A. Young, Ph.D., a researcher involved in the work from the Musculoskeletal Research Group at the Institute of Cellular Medicine at Newcastle University in Newcastle upon Tyne in the United Kingdom. "Our work provides a better understanding of the events that cause cartilage damage during osteoarthritis and provides hope that tailored drug development to prevent the progress of disease will improve the quality of life and mobility of many arthritis sufferers."
To make the discovery, Young and colleagues compared the extent to which DNA methylation was different in cartilage from patients suffering from osteoarthritis and healthy people of similar age. They found that at one small position, the gene for MMP13 had less DNA methylation in diseased patients. Then they confirmed that reduced methylation of this gene increases levels of the destructive enzyme MMP13.
"We've already seen how epigenetics has advanced our approach to cancer. Now we're seeing it with other diseases and even exercise." said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. "This study not only lays the groundwork for a new understanding of osteoarthritis, but also shows that the old 'either/or' nature v. nurture argument is outdated: epigenetics teaches us that nature (the daily wear and tear of joints) regulates nurture (the genes in our cartilage) to cause arthritis."
"Epigentics" appears to be gaining a lot of traction. Form nowhere, its now turning up in my alerts with increasing frequency. This press release on osteoporosis just showed up:
Quote:
UCLA researcher discovers epigenetic links in cell-fate decisions of adult stem cells
Finding could pave way toward treatments for bone diseases like osteoporosis
The ability to control whether certain stem cells ultimately become bone cells holds great promise for regenerative medicine and potential therapies aimed at treating metabolic bone diseases.
Now, UCLA School of Dentistry professor and leading cancer scientist Dr. Cun-Yu Wang and his research team have made a significant breakthrough in that direction. The scientists have discovered two key epigenetic regulating genes that govern the cell-fate determination of human bone marrow stem cells.
Wang's new research is featured on the cover of the July 6 issue of Cell Stem Cell, the affiliated journal of the International Society for Stem Cell Research.
The groundbreaking study grew out of Wang's desire to better understand the epigenetic regulation of stem cell differentiation, in which the structure of genes is modified while the sequence of the DNA is not. He and his team found that KDM4B and KDM6B, two gene-activating enzymes, can promote stem cells' differentiation into bone cells by removing methyl markers from histone proteins. This process occurs through the activation of certain genes favoring a commitment to one lineage and the concurrent deactivation of genes favoring other lineages.
The findings imply that chemical manipulation of these gene-activating enzymes may allow stem cells to differentiate specifically into bone cells, while inhibiting their differentiation into fat cells. The group's research could pave the way toward identifying potential therapeutic targets for stem cell–mediated regenerative medicine, as well as the treatment of bone disorders like osteoporosis, the most common type of metabolic bone disease.
"Through our recent discoveries on the lineage decisions of human bone marrow stem cells, we may be more effective in utilizing these stem cells for regenerative medicine for bone diseases such as osteoporosis, as well as for bone reconstruction," Wang said. "However, while we know certain genes must be turned on in order for the cells to become bone-forming cells, as opposed to fat cells, we have only a few clues as to how those genes are switched on."
The research group, through its study of aging mice, found that the two enzymes KDM4B and KDM6B could specifically activate genes that promote stem cell differentiation toward bone, while blocking the route toward fat.
"Interestingly, in our aged mice, as well as osteoporotic mice, we observed a higher amount of silencing histone methyl groups which were normally removed by the enzymes KDM4B and KDM6B in young and healthier mice," Wang said. "And since these enzymes can be easily modified chemically, they may become potential therapeutic targets in tissue regeneration and treatment for osteoporosis."
"The discovery that Dr. Wang and his team have made has considerable implications for craniofacial bone regeneration and treatment for osteoporosis," said Dr. No-Hee Park, dean of the UCLA School of Dentistry. "As a large portion of our population reaches an age where osteoporosis and gum disease could be major health problems, advancements in aging-related treatment are very valuable."
__________________ Craig Payne
__________________________________________________ ___________________________________ Follow me on Twitter | Run Junkie God put me on this earth to accomplish a certain number of things - right now I am so far behind, I will never die.
Multigenerational epigenetic adaptation of the hepatic wound-healing response
Müjdat Zeybel, Timothy Hardy, Yi K Wong, John C Mathers, Christopher R Fox, Agata Gackowska, Fiona Oakley, Alastair D Burt, Caroline L Wilson, Quentin M Anstee, Matt J Barter, Steven Masson, Ahmed M Elsharkawy, Derek A Mann & Jelena Mann Nature Medicine (2012) Published online 02 September 2012
Quote:
We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F1 and F2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor γ (PPAR-γ) and lower expression of the profibrogenic factor transforming growth factor β1 (TGF-β1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-γ chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis.
Press Release: Epigenetics emerges strongly as a clinical tool
Quote:
A study coordinated by Manel Esteller, published in Nature Reviews Genetics, highlights the success of this area of research to predict the behavior and weaknesses of tumors
The research team led by Manel Esteller, director of the Cancer Epigenetics and Biology Program at the Bellvitge Biomedical Research Institute (IDIBELL), professor of genetics at the University of Barcelona and ICREA researcher, has updated the latest findings in applied epigenetic in a review paper published in Nature Reviews Genetics.
There is a growing need for better biomarkers that allow early detection of human diseases, especially cancer. The markers can improve primary prevention, diagnosis and prognosis of disease. Furthermore, it is possible to predict which may be more effective treatments according to patient characteristics, which is known by the name of personalized medicine.
The genetic tests complementary to traditional methods have been used to improve the approach to various diseases, but in the last ten years Epigenetics has hardly emerged to help solve these clinical situations, as highlighted by the article. Epigenetics is the discipline for the study of the chemical changes in our genetic material and the same regulatory proteins. The most known epigenetic mark is the addition of a methyl group to the DNA.
The study notes that the last decade two tests based on the methylation of two genes, MGMT and GSTP1, have been proved vital in predicting brain tumors sensitive to the temozolomide drug and in distinguishing prostate cancer compared benign growth, respectively. Dr. Esteller points out that "the most exciting thing is that they are currently being identified new epigenetic biomarkers for predicting the performance and weaknesses of tumors at a fast pace." In this sense, the coordinator of the study cites the recent identification of epigenetic alterations in predictive genes as response to new generation drugs in leukemia and the fact that obtaining a "picture" of the DNA methylation pattern can expose unknown tumors that previously had a very poor prognosis.
Reference
Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nature Reviews Genetics, September 4, 2012.
Press Release: New evidence for epigenetic effects of diet on healthy aging
Quote:
New research in human volunteers has shown that molecular changes to our genes, known as epigenetic marks, are driven mainly by ageing but are also affected by what we eat.
The study showed that whilst age had the biggest effects on these molecular changes, selenium and vitamin D status reduced the accumulation of epigenetic changes, and high blood folate and obesity increased them. These findings support the idea that healthy ageing is affected by what we eat.
Researchers from the Institute of Food Research led by Dr Nigel Belshaw, working with Prof John Mathers and colleagues from Newcastle University, examined the cells lining the gut wall from volunteers attending colonoscopy clinic. The Institute of Food Research is strategically funded the Biotechnology and Biological Sciences Research Council and this study was also funded by the Food Standards Agency.
The study volunteers were free from cancer or inflammatory bowel disease and consumed their usual diet without any supplements. The researchers looked for specific epigenetic modifications of the volunteers' genes that have been associated with the earliest signs of the onset of bowel cancer – an age-related disease. These epigenetic marks, known as DNA methylation, do not alter the genetic code but affect whether the genes are turned on or off. These methylation marks are transmitted when cells divide, and some have been associated with the development of cancer. The investigators studied the relationship between the occurrence of these epigenetic marks at genes known to be affected in cancer, and factors including the volunteers' age, sex, body size and the levels of some nutrients in the volunteers' blood. The biggest influence on gene methylation was age. This fits with the fact that the biggest risk factor for bowel cancer is age, with risk increasing exponentially over 50 years old.
The findings, published in the journal Aging Cell, showed that men tended to have a higher frequency of these epigenetic changes than women, which is consistent with men being at a greater risk of bowel cancer. Volunteers with higher vitamin D status tended to show lower levels of methylation, and a similar effect was observed for selenium status. Again, this is consistent with the known links between higher vitamin D and selenium and reduced bowel cancer risk.
The B vitamin folate is essential for health, but in this study, high folate status was associated with increased levels of epigenetic changes linked with bowel cancer. These findings are consistent with some epidemiological studies suggesting that excessive folate intakes may increase risk in some people. The researchers intend to investigate the mechanism for the observed effect of folate on DNA methylation in a follow-up study.
Obesity is also a risk factor for bowel cancer. This study found relationships between body size (height, weight and waist circumference) and epigenetic changes. How excess body weight induces these epigenetic changes, and the consequences for gut health, are currently being investigated at IFR and in Newcastle University.
In summary, the results of this study support the hypothesis that ageing affects the epigenetic status of some genes and that these effects can be modulated by diet and body fatness.
Press Release:
More than 3,000 epigenetic switches control daily liver cycles
Salk findings may help explain connections between dietary schedules and chronic disease
Quote:
When it's dark, and we start to fall asleep, most of us think we're tired because our bodies need rest. Yet circadian rhythms affect our bodies not just on a global scale, but at the level of individual organs, and even genes.
Now, scientists at the Salk Institute have determined the specific genetic switches that sync liver activity to the circadian cycle. Their finding gives further insight into the mechanisms behind health-threatening conditions such as high blood sugar and high cholesterol.
"We know that genes in the liver turn on and off at different times of day and they're involved in metabolizing substances such as fat and cholesterol," says Satchidananda Panda, co-corresponding author on the paper and associate professor in Salk's Regulatory Biology Laboratory. "To understand what turns those genes on or off, we had to find the switches."
To their surprise, they discovered that among those switches was chromatin, the protein complex that tightly packages DNA in the cell nucleus. While chromatin is well known for the role it plays in controlling genes, it was not previously suspected of being affected by circadian cycles.
Panda and his colleagues, including Joseph R. Eckercircadian cycles, holder of the Salk International Council Chair in Genetics, report their results December 5 in Cell Metabolism.
Over the last ten years, scientists have begun to discover more about the relationship between circadian cycles and metabolism. Circadian cycles affect nearly every living organism, including plants, bacteria, insects and human beings.
"It's been known since the early eighteenth century that plants kept in darkness still open their leaves in 24 hour cycles. Similarly, human volunteers also maintain circadian rhythms in dark rooms. Now we're determining the regulatory processes that control those responses," says Ecker, who was recently elected a fellow of the American Association for the Advancement of Science for his work on the genetics of plant and human cells.
Panda offers an example of human circadian influenced behavior that is painfully familiar to all parents of newborns: Why do infants wake up in the middle of the night? It isn't because they aren't yet "trained" to a regular schedule, but because their internal circadian clocks haven't even developed.
"Once the clock is developed, the infant can naturally sleep through the night," Panda says. "On the other end of the scale, older people with dementia have sleep problems because their biological clock has degenerated."
In the case of humans and other vertebrates, a brain structure called the suprachiasmatic nucleus controls circadian responses. But there are also clocks throughout the body, including our visceral organs, that tell specific genes when to make the workhorse proteins that enable basic functions in our bodies, such as producing glucose for energy.
In the liver, genes that control the metabolism of fat and cholesterol turn on and off in sync with these clocks. But genes do not switch on and off by themselves. Their activity is regulated by the "epigenome," a set of molecules that signal to the genes how many proteins they should make, and, most importantly from the circadian point of view, when they should be made.
"We know that when we eat determines when a particular gene turns on or off, for example, if we eat only at nighttime, a gene that should be turned on during the day will turn on at night," Panda says.
For this reason, the epigenome is of particular interest for health, since we can control when we eat. An earlier study from Panda's lab, published last May in Cell Metabolism, suggested that we should observe a 16-hour fast between our evening and morning meals.
"In response to natural cycles, our body has evolved to make glucose at nighttime," Panda says. "But if on top of that you eat, you're creating excess glucose and that damages organs, which leads to diabetes. It's like over-charging a car battery. Bad things will happen."
In short, while we can't control what genes we're born with, we do have some influence over what they do. Nevertheless, the interplay between genome and epigenome is extremely complex. Panda, Ecker and their colleagues, including the paper's co-first authors Salk postdoctoral researchers, Christopher Vollmers and Robert J. Schmitz, did their studies in mice. In the mouse liver, they discovered more than 3,000 epigenomic elements, which regulate the circadian cycles of 14,492 genes. Comparing the mouse genome to the human genome, they find many of the same genes.
"Now that we know where the switches are, it brings us one step closer to understanding the mechanism of gene regulation," says Panda, "For example, it helps us restrict our search for other factors to particular regions of the genome. In other words, at least we now know to search in Alaska, rather than Australia. But Alaska's still a big place."
Other researchers on the study were: Jason Nathanson and Gene Yeo, of the University of California, San Diego
The work was supported by the Blasker Science and Technology Grant Award from the San Diego Foundation; the National Institutes of Health; the Mary K. Chapman Foundation; the Howard Hughes Medical Institute; the Gordon and Betty Moore Foundation; and the Pew Scholars Program in Biomedical Sciences.
Not exactly relevant to Podiatry or the diabetic foot, but this press release caught my eye this morning:
Study finds epigenetics, not genetics, underlies homosexuality
Quote:
KNOXVILLE – Epigenetics – how gene expression is regulated by temporary switches, called epi-marks – appears to be a critical and overlooked factor contributing to the long-standing puzzle of why homosexuality occurs.
According to the study, published online today in The Quarterly Review of Biology, sex-specific epi-marks, which normally do not pass between generations and are thus "erased," can lead to homosexuality when they escape erasure and are transmitted from father to daughter or mother to son.
From an evolutionary standpoint, homosexuality is a trait that would not be expected to develop and persist in the face of Darwinian natural selection. Homosexuality is nevertheless common for men and women in most cultures. Previous studies have shown that homosexuality runs in families, leading most researchers to presume a genetic underpinning of sexual preference. However, no major gene for homosexuality has been found despite numerous studies searching for a genetic connection.
In the current study, researchers from the Working Group on Intragenomic Conflict at the National Institute for Mathematical and Biological Synthesis (NIMBioS) integrated evolutionary theory with recent advances in the molecular regulation of gene expression and androgen-dependent sexual development to produce a biological and mathematical model that delineates the role of epigenetics in homosexuality.
Epi-marks constitute an extra layer of information attached to our genes' backbones that regulates their expression. While genes hold the instructions, epi-marks direct how those instructions are carried out – when, where and how much a gene is expressed during development. Epi-marks are usually produced anew each generation, but recent evidence demonstrates that they sometimes carryover between generations and thus can contribute to similarity among relatives, resembling the effect of shared genes.
Sex-specific epi-marks produced in early fetal development protect each sex from the substantial natural variation in testosterone that occurs during later fetal development. Sex-specific epi-marks stop girl fetuses from being masculinized when they experience atypically high testosterone, and vice versa for boy fetuses. Different epi-marks protect different sex-specific traits from being masculinized or feminized – some affect the genitals, others sexual identity, and yet others affect sexual partner preference. However, when these epi-marks are transmitted across generations from fathers to daughters or mothers to sons, they may cause reversed effects, such as the feminization of some traits in sons, such as sexual preference, and similarly a partial masculinization of daughters.
The study solves the evolutionary riddle of homosexuality, finding that "sexually antagonistic" epi-marks, which normally protect parents from natural variation in sex hormone levels during fetal development, sometimes carryover across generations and cause homosexuality in opposite-sex offspring. The mathematical modeling demonstrates that genes coding for these epi-marks can easily spread in the population because they always increase the fitness of the parent but only rarely escape erasure and reduce fitness in offspring.
"Transmission of sexually antagonistic epi-marks between generations is the most plausible evolutionary mechanism of the phenomenon of human homosexuality," said the study's co-author Sergey Gavrilets, NIMBioS' associate director for scientific activities and a professor at the University of Tennessee-Knoxville.
__________________ Craig Payne
__________________________________________________ ___________________________________ Follow me on Twitter | Run Junkie God put me on this earth to accomplish a certain number of things - right now I am so far behind, I will never die.
Press Release: Scientists discover how epigenetic information could be inherited
Research reveals the mechanism of epigenetic reprogramming
Quote:
New research reveals a potential way for how parents' experiences could be passed to their offspring's genes. The research was published today, 25 January, in the journal Science.
Epigenetics is a system that turns our genes on and off. The process works by chemical tags, known as epigenetic marks, attaching to DNA and telling a cell to either use or ignore a particular gene.
The most common epigenetic mark is a methyl group. When these groups fasten to DNA through a process called methylation they block the attachment of proteins which normally turn the genes on. As a result, the gene is turned off.
Scientists have witnessed epigenetic inheritance, the observation that offspring may inherit altered traits due to their parents' past experiences. For example, historical incidences of famine have resulted in health effects on the children and grandchildren of individuals who had restricted diets, possibly because of inheritance of altered epigenetic marks caused by a restricted diet.
However, it is thought that between each generation the epigenetic marks are erased in cells called primordial gene cells (PGC), the precursors to sperm and eggs. This 'reprogramming' allows all genes to be read afresh for each new person - leaving scientists to question how epigenetic inheritance could occur.
The new Cambridge study initially discovered how the DNA methylation marks are erased in PGCs, a question that has been under intense investigation over the past 10 years. The methylation marks are converted to hydroxymethylation which is then progressively diluted out as the cells divide. This process turns out to be remarkably efficient and seems to reset the genes for each new generation. Understanding the mechanism of epigenetic resetting could be exploited to deal with adult diseases linked with an accumulation of aberrant epigenetic marks, such as cancers, or in 'rejuvenating' aged cells.
However, the researchers, who were funded by the Wellcome Trust, also found that some rare methylation can 'escape' the reprogramming process and can thus be passed on to offspring – revealing how epigenetic inheritance could occur. This is important because aberrant methylation could accumulate at genes during a lifetime in response to environmental factors, such as chemical exposure or nutrition, and can cause abnormal use of genes, leading to disease. If these marks are then inherited by offspring, their genes could also be affected.
Dr Jamie Hackett from the University of Cambridge, who led the research, said: "Our research demonstrates how genes could retain some memory of their past experiences, revealing that one of the big barriers to the theory of epigenetic inheritance - that epigenetic information is erased between generations - should be reassessed."
"It seems that while the precursors to sperm and eggs are very effective in erasing most methylation marks, they are fallible and at a low frequency may allow some epigenetic information to be transmitted to subsequent generations. The inheritance of differential epigenetic information could potentially contribute to altered traits or disease susceptibility in offspring and future descendants."
"However, it is not yet clear what consequences, if any, epigenetic inheritance might have in humans. Further studies should give us a clearer understanding of the extent to which heritable traits can be derived from epigenetic inheritance, and not just from genes. That could have profound consequences for future generations."
Professor Azim Surani from the University of Cambridge, principal investigator of the research, said: "The new study has the potential to be exploited in two distinct ways. First, the work could provide information on how to erase aberrant epigenetic marks that may underlie some diseases in adults. Second, the study provides opportunities to address whether germ cells can acquire new epigenetic marks through environmental or dietary influences on parents that may evade erasure and be transmitted to subsequent generations, with potentially undesirable consequences."
The heritability of specific phenotypical traits relevant for physical performance has been extensively investigated and discussed by experts from various research fields. By deciphering the complete human DNA sequence, the human genome project has provided impressive insights into the genomic landscape. The hope that this information would reveal the origin of phenotypical traits relevant for physical performance or disease risks has proven overly optimistic, and it is still premature to refer to a 'post-genomic' era of biological science. Linking genomic regions with functions, phenotypical traits and variation in disease risk is now a major experimental bottleneck. The recent deluge of genome-wide association studies (GWAS) generates extensive lists of sequence variants and genes potentially linked to phenotypical traits, but functional insight is at best sparse. The focus of this review is on the complex mechanisms that modulate gene expression. A large fraction of these mechanisms is integrated into the field of epigenetics, mainly DNA methylation and histone modifications, which lead to persistent effects on the availability of DNA for transcription. With the exceptions of genomic imprinting and very rare cases of epigenetic inheritance, epigenetic modifications are not inherited transgenerationally. Along with their susceptibility to external influences, epigenetic patterns are highly specific to the individual and may represent pivotal control centers predisposing towards higher or lower physical performance capacities. In that context, we specifically review how epigenetics combined with classical genetics could broaden our knowledge of genotype-phenotype interactions. We discuss some of the shortcomings of GWAS and explain how epigenetic influences can mask the outcome of quantitative genetic studies. We consider epigenetic influences, such as genomic imprinting and epigenetic inheritance, as well as the life-long variability of epigenetic modification patterns and their potential impact on phenotype with special emphasis on traits related to physical performance. We suggest that epigenetic effects may also play a considerable role in the determination of athletic potential and these effects will need to be studied using more sophisticated quantitative genetic models. In the future, epigenetic status and its potential influence on athletic performance will have to be considered, explored and validated using well controlled model systems before we can begin to extrapolate new findings to complex and heterogeneous human populations. A combination of the fields of genomics, epigenomics and transcriptomics along with improved bioinformatics tools and precise phenotyping, as well as a precise classification of the test populations is required for future research to better understand the inter-relations of exercise physiology, performance traits and also susceptibility towards diseases. Only this combined input can provide the overall outlook necessary to decode the molecular foundation of physical performance
In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases.
Epigenetics and diabetic foot complications
Linear Mode
