Creative Minds: A New Mechanism for Epigenetics?

Keith Maggert

Keith Maggert

To learn more about how DNA and inheritance works, Keith Maggert has spent much of his nearly 30 years as a researcher studying what takes place not just within the DNA genome but also the subtle modifications of it. That’s where a stable of enzymes add chemical marks to DNA, turning individual genes on or off without changing their underlying sequence. What’s really intrigued Maggert is these “epigenetic” modifications are maintained through cell division and can even get passed down from parent to child over many generations. Like many researchers, he wants to know how it happens.

Maggert thinks there’s more to the story than scientists have realized. Now an associate professor at the University of Arizona College of Medicine, Tucson, he suspects that a prominent subcellular structure in the nucleus called the nucleolus also exerts powerful epigenetic effects. What’s different about the nucleolus, Maggert proposes, is it doesn’t affect genes one by one, a focal point of current epigenetic research. He thinks under some circumstances its epigenetic effects can activate many previously silenced, or “off” genes at once, sending cells and individuals on a different path toward health or disease.

Maggert has received a 2016 NIH Director’s Transformative Research Award to pursue this potentially new paradigm. If correct, it would transform current thinking in the field and provide an exciting new perspective to track epigenetics and its contributions to a wide range of human diseases, including cancer, cardiovascular disease, and neurodegenerative disorders.

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Study Finds No Safe Level of Smoking

Quit smoking

Thinkstock\Nastco

Many Americans who’ve smoked cigarettes have been successful in their efforts to quit. But there’s some bad news for those who’ve settled for just cutting back: new evidence shows there’s no safe amount of smoking. One cigarette a day, or even less than that, still poses significant risks to your health.

A study conducted by NIH researchers of more than 290,000 adults between the ages of 59 and 82 found that those who reported smoking less than one cigarette per day, on average, for most of their lives were nine times more likely to die from lung cancer than those who never smoked. The outlook was even worse for those who smoked between one and 10 cigarettes a day. Compared to never-smokers, they faced a 12 times greater risk of dying from lung cancer and 1½ times greater risk of dying of cardiovascular disease.

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Cardiometabolic Disease: Big Data Tackles a Big Health Problem

Cardiometabolic risk lociMore and more studies are popping up that demonstrate the power of Big Data analyses to get at the underlying molecular pathology of some of our most common diseases. A great example, which may have flown a bit under the radar during the summer holidays, involves cardiometabolic disease. It’s an umbrella term for common vascular and metabolic conditions, including hypertension, impaired glucose and lipid metabolism, excess belly fat, and inflammation. All of these components of cardiometabolic disease can increase a person’s risk for a heart attack or stroke.

In the study, an international research team tapped into the power of genomic data to develop clearer pictures of the complex biocircuitry in seven types of vascular and metabolic tissue known to be affected by cardiometabolic disease: the liver, the heart’s aortic root, visceral abdominal fat, subcutaneous fat, internal mammary artery, skeletal muscle, and blood. The researchers found that while some circuits might regulate the level of gene expression in just one tissue, that’s often not the case. In fact, the researchers’ computational models show that such genetic circuitry can be organized into super networks that work together to influence how multiple tissues carry out fundamental life processes, such as metabolizing glucose or regulating lipid levels. When these networks are perturbed, perhaps by things like inherited variants that affect gene expression, or environmental influences such as a high-carb diet, sedentary lifestyle, the aging process, or infectious disease, the researchers’ modeling work suggests that multiple tissues can be affected, resulting in chronic, systemic disorders including cardiometabolic disease.

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Precision Medicine: Using Genomic Data to Predict Drug Side Effects and Benefits

Gene Variant and Corornary Heart DiseasePeople with type 2 diabetes are at increased risk for heart attacks, stroke, and other forms of cardiovascular disease, and at an earlier age than other people. Several years ago, the Food and Drug Administration (FDA) recommended that drug developers take special care to show that potential drugs to treat diabetes don’t adversely affect the cardiovascular system [1]. The challenge in implementing that laudable exhortation is that a drug’s long-term health risks may not become clear until thousands or even tens of thousands of people have received it over the course of many years, sometimes even decades.

Now, a large international study, partly funded by NIH, offers some good news: proof-of-principle that “Big Data” tools can help to identify a drug’s potential side effects much earlier in the drug development process [2]. The study, which analyzed vast troves of genomic and clinical data collected over many years from more than 50,000 people with and without diabetes, indicates that anti-diabetes therapies that lower glucose by targeting the product of a specific gene, called GLP1R, are unlikely to boost the risk of cardiovascular disease. In fact, the evidence suggests that such drugs might even offer some protection against heart disease.

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Bioengineering: Big Potential in Tiny 3D Heart Chambers

iPS human heart

Caption: Heart microchamber generated from human iPS cells; cardiomyocytes (red), myofibroblasts (green), cell nuclei (blue) 
Credit: Zhen Ma, University of California, Berkeley

The adult human heart is about the size of a large fist, divided into four chambers that beat in precise harmony about 100,000 times a day to circulate blood throughout the body. That’s a very dynamic system, and also a very challenging one to study in real-time in the lab. Understanding how the heart forms within developing human embryos is another formidable challenge. So, you can see why researchers are excited by the creation of tiny, 3D heart chambers with the ability to exist (see image above) and even beat (see video below) in a lab dish, or as scientists  say “in vitro.”

iPS heart cells video

Credit: Zhen Ma et al., Nature Communications

To achieve this feat, an NIH-funded team from University of California, Berkeley, and Gladstone Institute of Cardiovascular Disease, San Francisco turned to human induced pluripotent stem (iPS) cell technology. The resulting heart chambers may be miniscule—measuring no more than a couple of hair-widths across—but they hold huge potential for everything from improving understanding of cardiac development to speeding drug toxicity screening.

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