Daily Archives: February 20, 2015

When scientists sequenced the human genome a decade ago, they hoped to unlock the code of life, the sequence of molecules lined up in every cell that, summed together, made a person a personand possibly reveal new ways to understand and treat diseases. But the resultsturned out to be opaque. Biologist Eric Lander, who helped lead the effort, famously summed up the results in seven words: Genome: Bought the book; hard to read.

So the research community went looking for CliffsNotes. A decade ago scientistsstarted looking into the epigenome, chemical modifications to DNA that tell cells which genes to turn on or turn off. This weekthat project got a huge data dump24 journal articles laying out what the genomicists know so far about 111 different cell types, the inner lives of brains, hearts, blood, and skin. It is giving us a view of the living, breathing genome in motion, as opposed to a static picture of DNA, says Manolis Kellis, a computational biologist at MIT who worked on two of the new papers.

Just about every cell in a human body has the same DNA, packaged into the same chromosomes. But cells differentiate, growing into different tissue types with different functions. The epigenome works through molecules like methyl and acetyl groups that wheedle their way into DNA, exposing different genes to the machinery that reads them and makes proteins. That helps control when or whether those proteins get made at all, and its also critical to that process of differentiation. In each cell type, it unravels just the right genes, says Brad Bernstein, a biologist at Harvard University. It unravels just the right switches.

One of the reasons the genome turned out to be so hard to read is that only about 1.5 percent of it actually consists of genes that encode for proteins. The other 98.5 percent? Scientists can read the sequenceATTATCG, or whateverbut they dont know what it actually does. Epigenomic maps like these new ones might help explain what that non-coding DNA is for. If the genome is a book, then the epigenome is like the post-it notes, dog-ears, and highlights that help you make sense of a particularly dense text. It wont tell you the meaning of Moby Dick, but it will tell you if theres a whale and wheres the boat, Kellis says.

Ideally, the epigenome will also have a lot to say about the origins and processes of some serious diseases with genetic components, like Crohns, diabetes, cancer, and Alzheimers. Scientists already know aboutgenetic variants associated with Alzheimers, but because those variants arent in the protein-coding part of the genome, no one knew what they did. Thanks to epigenomic maps from mice and human brain cells, Kellis has found that they have something to do with the immune system. Those genetic abnormalities, it seems, predispose you to Alzheimers. That basically means that the immune genes and regulatory regions are not simply a consequence of the disease, but in fact they are drivers, Kellis says. Thats something people were starting to suspect, but no one had actually shown at this level.

The epigenomic mapsmay evenhelp treatcancers. Doctors often tailor therapies to specific types of tumors, but in manycases, oncologists dontknowwhere a particular cancer originatedwhich makes treatment a crap shoot. But epigenomic maps can help them identify the origin of these mysterious cancers. Tumor cells are rife with mutations, it turns out, distributed all along the cells DNA. Healthy cells package DNAitself a long, winding strandby further winding it, packing it like an overcranked rubber band. In that form, the DNA is called chromatin. More tightly-wound parts are hidden, but looser sections are exposed and accessible to a cells normal DNA-repair machinerywhich means mutations there get fixed more often, creating a chromatin mutation pattern specific to individual cell types. In the new study, researchers discovered that mutation patterns in a cancer cell correspond with chromatin structure. That means thatif you can match a tumors mutation pattern with a knownchromatin structure, you know that the tumor came from that particular cell typeand a physician canprescribe the righttreatment.

Over a longer term, understanding epigenetic changes might even provide insight into the nature-versus-nurture debate. Everything from nutrition to chemical exposures can affect the epigenome. Yet epigenetic changesfor example, molecules like methyl groups working their way into genescan sometimes get passed on to offspring. Thats startling, and seems almost counter to basic evolutionary science. So scientists want to understand the relationship between the genome and the epigenome, and how environment and genetic predilections can intertwine.

But even with this huge set of papers, the research has a long way to go. The goal of the International Human Epigenome Consortium is to map more than 1,000 cell types and then compare how individual people varyhow one persons epigenome differs from another. Thats the job, says Kellis, that I think will occupy us for at least the next decade. The genome isnt just hard to readit also takes a long time.

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Reading Our Genome Is Tough, But Epigenetics Is Giving Us Valuable Clues

Single-letter genetic variations within parts of the genome once dismissed as 'junk DNA' can increase cancer risk through wormhole-like effects on far-off genes, new research shows.

Researchers found that DNA sequences within 'gene deserts' -- so called because they are completely devoid of genes -- can regulate gene activity elsewhere by forming DNA loops across relatively large distances.

The study, led by scientists at The Institute of Cancer Research, London, helps solve a mystery about how genetic variations in parts of the genome that don't appear to be doing very much can increase cancer risk.

Researchers developed a new technique to study the looping interactions and discovered that single-letter DNA variations linked to the development of bowel cancer were found in regions of the genome involved in DNA looping.

Their study, published today in Nature Communications, is the first to look comprehensively at these DNA interactions specifically in bowel cancer cells, and has implications for the study of other complex genetic diseases.

It was funded by the EU, Cancer Research UK, Leukaemia & Lymphoma Research, and The Institute of Cancer Research (ICR).

The researchers developed a technique called Capture Hi-C to investigate long-range physical interactions between stretches of DNA -- allowing them to look at how specific areas of chromosomes interact physically in more detail than ever before. Previous techniques used to investigate long-range DNA interactions were not sensitive enough to produce definitive results.

The researchers assessed 14 regions of DNA that contain single-letter variations previously linked to bowel cancer risk. They detected significant long-range interactions for all 14 regions, confirming their role in gene regulation.

These interactions are important because they can control how genes behave, and alterations in gene behaviour can lead to cancer -- in fact most genetic variations that have been linked to cancer risk are not in genes themselves, but in the areas of the genome that regulate them.

Study leader Professor Richard Houlston, Professor of Molecular and Population Genetics at The Institute of Cancer Research, London, said: "Our new technique shows that genetic variations are able to increase cancer risk through long-range looping interactions with cancer-causing genes elsewhere in the genome. It is sometimes described as analogous to a wormhole, where distortions in space and time could in theory bring together distant parts of the universe.

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Cancer risk linked to DNA 'wormholes'

"Alu" sequences are small repetitive elements representing about 10% of our genome. Because of their ability to move around the genome, these "jumping genes" are considered as real motors of evolution. However, they were considered for a long time as "junk" DNA, because, although they are transcribed into RNA, they encode no proteins and do not seem to participate actively in the cell's functions. Now, the group of Katharina Strub, professor at the Faculty of Science of the University of Geneva (UNIGE), Switzerland, has uncovered two key functions of Alu RNAs in human cells, which are the subject of two different articles published in Nucleic Acids Research. Alu RNA can bind to specific proteins forming a complex called Alu RNP. On the one hand, this complex allows the cells to adapt to stress caused for example by chemical poisoning or viral infection. On the other hand, the same complex plays a role in protein synthesis by regulating the number of active ribosomes, suggesting that it could be part of the innate system of cellular defense against certain viruses.

Having emerged within mammals from a common ancestor, the genomic "Alu" elements multiplied during evolution to the point of representing about 10% of the primate and human genomes, whereas they are about ten-fold less abundant in rodents. These small repetitive elements are an important source of genetic variations, due to their ability to move freely around the genome, and they are therefore considered as motors of evolution, Apart from this essential function, what could be the advantage for the human genome to tolerate such a large number of Alu elements, which encode no proteins?

Alu elements are transcribed into RNA molecules, which bind specific proteins to form a complex called Alu RNP. "Alu RNP levels increases strongly in response to stress caused for example by poisoning or viral infections. The function of the Alu RNP is not known and we wished to determine whether these complexes play an active role in the stress response," explains Katharina Strub, professor at the Department of Cell Biology of the UNIGE.

A protection against toxics

Cells experiencing a stress react by temporarily forming numerous "stress granules," whose function is to sequester cell signaling proteins to prevent cell death. In addition, these granules accumulate various factors necessary for the synthesis of new proteins, while waiting for the situation to normalize. "When we treat human cells with arsenic, the Alu RNP complexes dissociate from their proteins called SRP9/14. The released proteins then bind key components of the protein synthesis machinery and participate in the formation of stress granules," says Audrey Berger, researcher and first author of the first article.

How does Alu RNA help cells to return to normality? "Following stress, cells actively produce a lot of Alu RNA, which will associate with the SRP9/14 proteins to form Alu RNPs. This will release components sequestered in stress granules and allows protein synthesis to resume," indicates the biologist. Thus, Alu RNAs actively participate in stress granule formation and dissolution.

Against viruses too

When viruses such as HIV and hepatitis C infect cells, they shut down cellular protein synthesis to hijack the protein synthesis machinery to their own profit. Many viral RNAs indeed possess specific sequences called IRES, which allow the direct recruitment of ribosomes to produce viral proteins instead of cellular proteins.

Based on the second study of the research group, Alu RNP complexes also play a protective role in case of infection. "They interfere with the formation of viral proteins, by inactivating the ribosomes before they are recruited to the viral RNA via the IRES," explains Elena Ivanova, researcher and first author of the second article. The cells in which Alu RNA expression increases following certain types of infection would thus produce a lot fewer viral particles.

As suggested by the authors, Alu RNP complexes could therefore be a component of the innate system of cellular defense against certain viruses. These complexes are also used by cells to adapt to conditions of stress and they play a role in the process of protein synthesis, by regulating the number of active ribosomes.

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Jumping genes have essential biological functions

DNA is a long code of instructions to build every tissue in our body. But there are little markers along the way that tell cells how to read the DNA. And those markers turn genes on and off, which could affect disease or even your personal preferences. Image by Scott Tysick/Getty Images

Each cell in your body has the same DNA, but they dont all follow the same instructions. Some become blood cells; others become brain cells or muscle tissue. But if the DNA has a mistake or the cells turn on the wrong set of genes, that can lead to disease.

So how do cells decide which genes to turn on and which to turn off in different tissues? Thats the basis of epigenomics, chemical markers on the DNA and its packaging. Epigenomics is the focus of this weeks issue of the journal Nature, which includes a collection of papers from the Roadmap Epigenomics Program, a reference map of these modifications across a variety of human cells built by an international collaboration of scientists and researchers. Eight papers from the project are featured this weeks issue of Nature, and 16 others are published this week in other Nature journals.

The genome contains all these genes, but it doesnt tell you anything about how theyre working. These maps are giving snapshots of the genome in action, said Lisa Helbling Chadwick, Roadmap Epigenomics Program team leader and program director at the National Institute of Environmental Health Sciences. Our cells all have the same instruction book, but they have very different functions. How do they take this one set of instructions and come out so different?

Think of it this way, said Manolis Kellis, professor of computer science at MIT and author of several of the papers on the issue: You start as a single cell, a zygote with a 6.5 foot-long string of DNA with billions of letters. That genetic material contains all the instructions from mom and dad that youll need throughout your lifetime. But you dont need it all at once.

Enter the epigenome. Think of the epigenome, Kellis said, as a set of color-coded Post-It notes stuck to that DNA. These Post-Its are chemical modifications that can be read by different proteins and control how the DNA is getting used.

So continuing this analogy, green Post-It notes might point to the genes that are on, and yellow notes might point to the genes that are off. Orange notes might point to the control switches that help turn these genes on and off.

All cells in our body contain a copy of the same genome, the book of life that we inherited from our parents. However, each cell is using the book in a slightly different way. Theyre all reading different chapters, bookmarking different pages, and highlighting different paragraphs and words, Kellis said. The human epigenome is this collection of marks placed on the genome in each cell type, in the form of chemical modifications on the DNA itself, and on the packaging that holds DNA together.

The journal Nature explained it in musical terms:

On the surface, about 99.9 percent of our genome is the same from person to person, Kellis said. That still leaves .1 percent, or about 3 million letters that are different, scattered throughout all our genes. But it takes nature and nurture to make us who we are, he said. If DNA is the nature part of the equation, then epigenomics straddles the line between nature and nurture. Your genome was inherited, but your epigenome is partly shaped by environment and lifestyle.

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A detailed new map of our genome in action