For more than a decade, scientists have had access to a reference human genome. Now, the equivalent for the epigenome has been published, in a collection of papers appearing on 18 February in Nature and several other journals. A large international group of researchers has put together 111 epigenomes from different human cell types, including all the major organs, immune cells and embryonic stem cells. The team has also assembled epigenomes for induced pluripotent stem cells — cells that are derived from adult cells and coaxed into becoming capable of developing into almost any other type of cell in the body.
14. And from those who call
themselves Christians, We took their covenant, but they have abandoned a good
part of the Message that was sent to them. So We planted amongst them enmity
and hatred till the Day of Resurrection (when they discarded Allah's Book,
disobeyed Allah's Messengers and His Orders and transgressed beyond bounds in
Allah's disobedience), and Allah will inform them of what they used to do.
15. O people of the
Scripture (Jews and Christians)! Now has come to you Our Messenger (Muhammad ) explaining to you much of that which
you used to hide from the Scripture and passing over (i.e. leaving out
without explaining) much. Indeed, there has come to you from Allah a light
(Prophet Muhammad ) and a
plain Book (this Qur'an).
16. Wherewith Allah guides
all those who seek His Good Pleasure to ways of peace, and He brings them out
of darkness by His Will unto light and guides them to a Straight Way (Islamic
Monotheism). 5. Surah Al-Ma'idah (The Table Spread with Food)
The researchers looked for features including chemical tweaks to DNA that prime genes to be switched on or off, and alterations to the 'histone' proteins around which DNA is wrapped. Chemical or structural modifications to histones can affect which genes the cellular machinery translates into proteins and which remain silent. Such epigenetic changes can dramatically affect a cell’s behaviour and function.
The epigenomes also contain hints of how epigenetic changes could be involved in diseases, including cancer, Alzheimer's disease and autoimmune diseases.
Cambridge, Massachusetts - The sequencing of the human genome laid the foundation for the study of genetic variation and its links to a wide range of diseases. But the genome itself is only part of the story, as genes can be switched on and off by a range of chemical modifications, known as “epigenetic marks.”
Now, a decade after the human genome was sequenced, the National Institutes of Health’s Roadmap Epigenomics Consortium has created a similar map of the human epigenome.
Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory and of the Broad Institute, led the effort to integrate and analyze the datasets produced by the project, which constitute the most comprehensive view of the human epigenome to date.
In a paper published today in the journal Nature, Kellis and his colleagues report 111 reference human epigenomes and study their regulatory circuitry, in a bid to understand their role in human traits and diseases.
“The consortium set out to systematically characterize the human epigenomic landscape, across diverse tissues and cell types,” Kellis says. “Given the enormity of the task, that meant bringing together multiple mapping centers and profiling a wide range of cell and tissue samples, to capture the diversity of the human epigenome.”
150 billion genomic sequences
The researchers generated 2,805 genome-wide datasets, encompassing a total of 150 billion sequencing reads, corresponding to 3,174-fold coverage of the human genome. These captured modifications of both the DNA itself, and of the histone proteins around which DNA is wrapped to form a structure known as chromatin.
Kellis and his team then developed and applied machine-learning algorithms that could translate these datasets into a reference map in each of the 111 cell types and tissues. The algorithms distinguished different classes of epigenomic modifications and used them to annotate the genomic regions active in each sample, and in particular regulatory elements that control where and when different genes are expressed.
“Different combinations of epigenetic marks characterize different regions of the genome, reflecting the specific functions that they play in each cell,” Kellis says. “By studying these combinations systematically, we can learn the language of the epigenome, and what it is telling us about both the activity and the function of each genomic region in each of the cell types.”
The researchers distinguished 15 different epigenomic signatures, or chromatin states, reflecting active, repressed, poised, transcribed, and inactive regions of the genome in each cell type. About 5 percent of each reference epigenome showed signatures associated with a regulatory function.
“Chromatin states allowed us to summarize the complexity of diverse epigenomic marks into a small number of common patterns,” Kellis says. “We could then interpret the biological functions of these patterns.”
Epigenomic dynamics
The researchers then studied how these chromatin states varied across different types of cells and tissues. This allowed them to group cell types with similar regulatory circuitry. They also grouped together regulatory regions that are active in the same types of cells. In this way they could begin to reveal the building blocks of regulatory circuits.
“Unlike the genome, which is mostly unchanged across cell types, the epigenome is extremely dynamic, reflecting the specialization of each cell type, such as neurons, heart, muscle, liver, skin, blood, or immune cells,” Kellis says. “By studying which regions turn on and off in the same cell types, we can gain insights into gene regulation.”
The researchers grouped 2 million predicted regulatory regions into 200 sets, or modules, which appeared to be acting in a coordinated manner across different types of cells. They found that 100 of these modules contained common sequence patterns, known as regulatory motifs, which may be responsible for their ability to work together in this way.
“Exploiting the predicted regulators and their motifs can help dissect the circuitry of different tissues and cells,” Kellis says.
The researchers also compared these epigenomic signatures with groups of genetic variants that are associated with different human traits and diseases. This allowed them to produce a map of the tissue and cell types that are most relevant to each trait or disease.
“We found that genetic variants are found in regulatory regions known as enhancers, which are activated only in certain types of cell and tissue,” Kellis says. “This suggests that many genetic variants affect the regulatory circuitry of the cell, possibly disrupting gene functions by altering tissue-specific gene expression levels.”
Tissue-specific enhancers affect 58 traits
The researchers found significant tissue-specific enhancer signatures for genetic variants associated with 58 different traits. These included height, in embryonic stem cells; multiple sclerosis, in immune cells; attention deficit disorder, in brain tissues; blood pressure, in heart tissues; fasting glucose, in pancreatic islets; cholesterol, in liver tissue; and Alzheimer’s disease, in CD14 monocytes.
“This unbiased view allows researchers to focus on relevant cells and tissues that may have been otherwise overlooked when studying a particular disease,” Kellis says. “The regulatory circuitry of a diverse range of cells can contribute to diseases that manifest in seemingly unexpected organs.”
Using these circuits to understand the molecular basis of human disorders will take many years and the effort of many labs, Kellis says. “Our results provide an invaluable map, and a rich set of hypotheses, which can help guide these studies.”
Wolf Reik, head of the epigenetics research program at the Babraham Institute in the U.K., who was not involved in the research, says the project is an exciting resource for the biomedical community worldwide.
“Important epigenetic marks were mapped systematically in many human cell types and tissues,” Reik says. “Integrative analysis of these epigenomes provides a global map toward understanding fundamental developmental and disease processes in humans.”
Since the emergence of epigenomics, which is the study of how epigenetic modifications affect the genetic material of cells or the entire organism, geneticists have discovered that the human genome is a lot more complex than they have ever imagined. For example, DNA sequencing technologies that are currently available to mainstream geneticists can only decode roughly 21,000 known genes that are involved in protein synthesis in the human body. This only decodes a very small percentage of the human genome.
The 21,000 known genes that are involved in protein synthesis make up nearly 1.5 percent of the human body’s DNA. This means that roughly 98.5 percent of the human DNA structure, which is often referred to as “junk DNA”, is yet to be decoded. However, certain advanced DNA sequencing technologies that aren’t available to mainstream geneticists have decoded the human genome beyond the 21,000 known genes.
The roles of genetic switches
Geneticists have discovered that the human genome consists of not only genes, but also a highly complex genetic switch system, composing of millions of genetic switches. These genetic switches are used by the human body to turn genes on and off. So far, geneticists have found slightly more than 4 million switching sites, which only cover roughly 8.5 percent of the human genome.
Each of the millions of genetic switches in the human genome affects certain specific gene activity and expression. When these genetic switches are defected and not working in harmony with the other systems of the human DNA, it can lead to faulty gene activity, which can cause health problems.
Genetic switches, food toxins, environmental toxins, and electromagnetic pollution
There are many things that can cause genetic switches to not work properly. One of the most effective things is genetically modified organism (GMO). Certain geneticists believe that the unnatural genetic materials in GMO can interfere with the natural functions of genetic switches in the human body. This is why GMO has been linked to all sorts of health conditions, including but not limited to infertility, birth defects, immune disorders, growth problems, premature aging, and cancer.
Besides GMO, food toxins, environmental toxins, and electromagnetic pollution can also interfere with gene activity and expression. Electromagnetic pollution is very effective at disharmonizing the natural frequencies of the human body. To learn about how electromagnetic pollution harms your body, read my informative article titled Frequency Healing and Electromagnetic Pollution.
How natural nutrients heal genes
Certain scientific studies have shown that by “tweaking” the epigenome of an organism using nutrients, they can reverse damages done to the genes of that organism. Other scientific studies have found that the way an offspring is raised and nurtured can affect the offspring’s genes in positive and negative ways.
The epigenome is just as critical to the development of humans as is the genome. For example, by changing the diet of genetically fat and yellow agouti mice to one rich in methyl donors, found in onions, garlic, and beets, researchers have found that they could change the offspring to slim and brown mice. By epigenetic intervention, they had modulated the critical agouti gene, dramatically changing the mice’s offspring. Nutrition was responsible for dimming the gene’s deleterious effects, from fat and yellow mice to mice that are normal, slim, and brown. (source: Eversole, Finley. Energy Medicine Technologies: Ozone Healing, Microcrystals, Frequency Therapy, and the Future of Health. Inner Traditions. Rochester, Vermont, 2013.)
Epigenomics is still somewhat new but it is already showing some amazing potential for healing all sorts of health conditions. With more research in epigenomics and better understanding of how genes work, geneticists will soon be able to reverse cancer, diabetes, Alzheimer’s, and other “incurable diseases”.
In what may be a big step forward in human biology, scientists are issuing the first comprehensive map of "human epigenomes" -- the range of chemical and structural shifts that determine how genes govern health.
The new map is the result of years of work by an international consortium of researchers. Experts say the new data will help scientists better understand how genetic disruption affects a wide range of illnesses, includingautism, heart disease and cancer.
"The DNA sequence of the human genome is identical in all cells of the body, but cell types such as heart, brain or skin cells have unique characteristics and are uniquely susceptible to various diseases," researcher Joseph Costello, of the University of California, San Francisco, explained in a university news release.
He said that epigenomic factors effectively "allow cells carrying the same DNA to differentiate into the more than 200 types found in the human body."
By mapping the mechanics behind 111 key patterns of gene expression (activation), the research team hopes it can shed light on how that differentiation process works -- for either good or ill.
The long-term goal, the researchers said, is to harness this new data to find better treatments for a wide range of cancers, autoimmune disorders and other illnesses that affect critical organs, such as the heart, brain or skin.
Costello is a member of the Helen Diller Family Comprehensive Cancer Center and is one of four directors of the U.S. National Institutes of Health's Roadmap Epigenome Mapping Centers (REMC). The REMC consortium includes hundreds of researchers from the University of California, Santa Cruz (UCSC), the University of Southern California (USC), and Washington University in St. Louis (WUSTL). Canadian members include both the Michael Smith Genome Sciences Centre and the University of British Columbia (UBC), both based in Vancouver, British Columbia.
The group published the new map online Feb. 18 in the journal Nature, accompanied by simultaneous publication in six other sister journals.
The entire effort began back in 2006. Since that time, REMC has focused its research on the stability and instability of chemical markers found on the spaghetti-like strands of DNA that are tucked into every human cell.
As the team explained, when everything is going well, these markers keep genes functioning as they should. However, they're vulnerable to environmental assault -- factors such as exposure to toxins, bad diets or aging -- and can mutate.
When they mutate, a cell's DNA can be activated (or fail to activate), leading to potentially harmful shifts in gene activity, the researchers said.
With such shifts comes the risk for disease.
The new epigenomic map lays out how these changes occur in several types of cells, including sperm cells, breast cells, blood cells, brain cells and skin cells.
All of the new information is being placed at the fingertips of scientists worldwide, via an online repository for all of the REMC's published data.
The hope is that scientists working in disparate fields can dip into the databank and better coordinate and complement each other's work.
"You've had cancer researchers studying the genome -- the role of mutations, deletions and so on -- and others studying epigenomes," Costello said. "They've almost been working on parallel tracks, and they didn't talk to each other all that much."
However, "over the past five or six years, there's been a reframing of the discussion," he said. That change in focus has led researchers and drug manufacturers to better appreciate the importance of the epigenome when considering both disease risk and potential new treatments, he added.
THE nature versus nurture debate is getting a facelift this week, with the publication of a genetic map that promises to tell us which bits of us are set in stone by our DNA, and which bits we can affect by how we live our lives.
The new "epigenomic" map doesn't just look at genes, but also the instructions that govern them. Compiled by a consortium of biologists and computer scientists, this information will allow doctors to pinpoint precisely which cells in the body are responsible for various diseases. It might also reveal how to adjust your lifestyle to counter a genetic predisposition to a particular disease.
"The epigenome is the additional information our cells have on top of genetic information," says lead researcher Manolis Kellis of the Massachusetts Institute of Technology. It is made of chemical tags that are attached to DNA and its packaging. These tags act like genetic controllers, influencing whether a gene is switched on or off, and play an instrumental role in shaping our bodies and disease.
Researchers are still figuring out exactly how and when epigenetic tags are added to our DNA, but the process appears to depend on environmental cues. We inherit some tags from our parents, but what a mother eats during pregnancy, for instance, might also change her baby's epigenome. Others tags relate to the environment we are exposed to as children and adults. "The epigenome sits in a very special place between nature and nurture," says Kellis.
Each cell type in our body has a different epigenome – in fact, the DNA tags are the reason why our cells come in such different shapes and sizes despite having exactly the same DNA. So for its map, the Roadmap Epigenomics Consortium collected thousands of cells from different adult and embryonic tissues, and meticulously analysed all the tags.
So far, they have produced 127 epigenomes, each corresponding to a different cell type, from brain cells to skin cells. That's a big advance on the 16 published in 2012 by the ENCODE project, which are included in the new map.
The consortium also cross-referenced these healthy epigenomes with previous data on the genetic components of dozens of diseases, including type 1 diabetes, Crohn's disease, high blood pressure, inflammatory bowel disease and Alzheimer's disease (see "Alzheimer's epigenetics").
The results, says Kellis, allow doctors to see what cell types are likely to be disrupted in people with these conditions. For instance, they suggest disruptions in the epigenome of the brain's cingulate gyrus cells may play a role in attention deficit hyperactivity disorder (Nature, DOI: 10.1038/nature14248).
Richard Meehan of the University of Edinburgh, UK, says the work offers "incredibly valuable information which will be absorbed and debated for years to come". He suggests that one day doctors will look at your epigenomes during routine health checks to suss out how the nature versus nurture battle is playing out inside your cells. These scans would reveal your genetic predisposition to certain conditions, and how your lifestyle is affecting those risks.
By adjusting your choices accordingly, you will be able to delay disease, or minimise its effects for as long as possible. "It's not going to move any further forward the point at which your life ends, but make the years up to that point – years that are spent in physical decline – a whole lot better," says Meehan.
"You see this on Star Trek," he adds. "Nobody lives any longer but they just seem to be healthier up to the point where life, unfortunately, passes away."
Late last year, scientists unveiled the complete genome of a femaleNeanderthal whose 130,000-year-old toe bone had been found in a cave in Siberia. As it turned out, her sequence of some 3 billion DNA letters was not all that much different from mine or yours. The researchers identified only about 35,000 places in the genome where all modern humans differ from our ancient hominid cousins. And only 3,000 of those were changes that could impact how genes are turned on and off.
But if our DNA is so similar to Neanderthals’, why were they so…different? They were brawnier than our ancestors, with short but muscular limbs, and big noses and eyebrows. They didn’t carry certain genetic variants that put modern humans at risk of autoimmune disease and celiac disease. And although they lived alongside our ancestors as the latter migrated into Europe, for some reason the Neanderthals didn’t survive.
Part of the answer undoubtedly lies in the way the Neanderthal genome actually worked — a complex process that depends not only on the underlying DNA code, but on the way genes get turned on and off. DNA molecules are constantly interacting with chemicals that control which genes can be activated. For example, a methyl group (one carbon and three hydrogen atoms) can latch on to the genome and help switch on or off the expression of nearby genes.
This dynamic layer of genome regulation, known as the ‘epigenome’, has received a ton of scientific attention in the last few decades. Researchers have claimed that epigenetics can explain (among many other things) how the placenta works, and why some people develop autism, and why enduring a famine in childhood might affect the health of one’s future grandchildren. A commentary in last week’s issue of Science suggests that epigenetics may also hold the key to interpreting ancient genomes, including those of the Neanderthal, a 4,000-year-old Eskimo, and an 800-year-old plant.
It’s crazy, really, that scientists can glean anything from such old, old DNA. To put together the Neanderthal genome scientists had to combine many DNA fragments painstakingly extracted from bits of bones. But these DNA sequences also carried hints of the past epigenome.
DNA methylation usually happens on DNA bases called cytosines. As it turns out, cytosines decay differently depending on whether they are methylated. The cytosines that once carried methyl groups turned into a chemical called thymine, whereas those that were not methylated turned into a different chemical, called uracil. By measuring thymine, then, researchers can estimate the amount of DNA methylation in ancient samples.
In May a team of researchers did exactly that to the Neanderthal genome, comparing its thymine profile to that of present-day people. As they published in Science, the scientists found that the overall methylation map was very similar between the two species, showing that their thymine trick was indeed a good proxy of methylation. But they also found intriguing differences. Unlike modern humans, Neanderthals carried a lot of methylation on the HOXD9 and HOXD10 genes, which are both known to be involved in limb development. This might explain some of the anatomical differences between the species, the authors say. What’s more, the genes that were methylated differently in Neanderthals and modern humans are nearly twice as likely to be linked to diseases, and particularly brain disorders.
In another recent study, researchers used similar epigenetic sleuthing on a Paleo-Eskimo found in Greenland. There are certain places in the genome, called ‘clock CpG sites’, in which methylation levels correlate predictably with age. By looking at the Eskimo’s thymine profile at these sites (gleaned from a 4,000-year-old tuft of hair), the researchers discovered that the guy likely died in his 50s.
Most of the controversy swirling around modern epigenomes relates to the question of just how readily our genes respond to changes in the environment. Somewhat amazingly, that same question can be investigated with ancient epigenomes. In a study published last month, researchers estimated the methylation levels of barley samples — ranging from 500 to 2,500 years old — found in an archaeological site in southern Egypt. The samples showed steadily decreasing levels of methylation with age (which is a clear demonstration of the aforementioned cytosine decay process, not a sign of rapidly changing methylation patterns). But there was one exception: An 800-year-old sample, which had tested positive for a killer infection called the Barley Stripe Mosaic Virus, had far higher levels of DNA methylation than an uninfected sample of the same age. It’s a neat illustration of ancient epigenomes revealing ancient exposures.
I don’t want to make too much of this approach. Scientists still don’t really know how to interpret epigenetic changes in living people (whose diet, exposures and medical history can be tracked, however crudely). What epigenetic differences say about ancient species is even more mysterious. All the same, it’s pretty incredible to think of the long biological histories that scientists manage to dig out of ice and rock.
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