May 9, 2013 Scientists have long known that control mechanisms known collectively as "epigenetics" play a critical role in human development, but they did not know precisely how alterations in this extra layer of biochemical instructions in DNA contribute to development.

Now, in the first comprehensive analysis of epigenetic changes that occur during development, a multi-institutional group of scientists, including several from the Salk Institute for Biological Studies, has discovered how modifications in key epigenetic markers influence human embryonic stem cells as they differentiate into specialized cells in the body. The findings were published May 9 in Cell.

"Our findings help us to understand processes that occur during early human development and the differentiation of a stem cell into specialized cells, which ultimately form tissues in the body," says co-lead author Joseph R. Ecker, a professor and director of Salk's Plant Molecular and Cellular Biology Laboratory and holder of the Salk International Council Chair in Genetics.

Scientists have established that the gene expression program encoded in DNA is carried out by proteins that bind to regulatory genes and modulate gene expression in response to environmental cues. Growing evidence now shows that maintenance of this process depends on epigenetic marks such as DNA methylation and chromatin modifications, biochemical processes that alter gene expression as cells divide and differentiate from embryonic stem cells into specific tissues. Epigenetic modifications -- collectively known as the epigenome -- control which genes are turned on or off without changing the letters of the DNA alphabet (A-T-C-G), providing cells with an additional tool to fine-tune how genes control the cellular machinery.

In their study, the Salk researchers and their collaborators from several prominent research institutions across the United States examined the beginning state of cells, before and after they developed into specific cell types. Starting with a single cell type -- the H1 human embryonic stem cell, the most widely studied stem cell line to date -- the team followed the cells' epigenome from development to different cell states, looking at the dynamics in changes to epigenetic marks from one state to another. Were they methylated, an essential process for normal development, or unmethylated? What happened to the cells during development? What regulatory processes occurred in the cell lineage?

The scientists found sections of the DNA that activate regulatory genes, which in turn control the activity of other genes, tend to have different amounts of letters of the DNA alphabet, "C" and "G" specifically, depending on when these regulatory genes are turned on during development. Additionally, regulatory genes that control early development are often located on stretches of DNA called methylation valleys, or DMVs, that are generally CG rich and devoid of epigenetic chemical modifications known as methylation.

Consequently, these genes have to be regulated by another epigenetic mechanism, which the authors found were chemical changes called chromatin modifications. Chromatin is the mass of material -- DNA and proteins -- in a cell's nucleus that helps to control gene expression.

On the other hand, genes active in more mature cells whose tissue type is already determined tend to be CG poor and regulated by DNA methylation. The results suggest that distinct epigenetic mechanisms regulate early and late states of embryonic stem cell differentiation.

"Epigenomic studies of how stem cells differentiate into distinct cell types are a great way to understand early development of animals," says Ecker, who is also a Howard Hughes Medical Institute and Gordon and Betty Moore Foundation Investigator. "If we understand how these cells' lineages originate, we can understand if something goes right or wrong during differentiation. It's a very basic study, but there are implications for being able to produce good quality cell types for various therapies."

For example, says Matthew Schultz, a graduate student in Ecker's lab, "understanding how development plays out normally could give us clues about how to reverse the process and turn normal adult cells into stem cells to regenerate tissues."

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Epigenomics of stem cells that mimic early human development charted

Professor Shaun McColl says new treatment for multiple sclerosis lies within modified adult stem cells. Picture: Dean Martin Source: adelaidenow

A POTENTIAL new treatment for multiple sclerosis lies within modified adult stem cells, University of Adelaide researchers say.

The researchers hope using stem cells from fat tissue - to send cells with anti-inflammatory properties directly to the damaged site in the central nervous system - will be able to treat the autoimmune disease.

Director of the Centre for Molecular Pathology, Professor Shaun McColl, said treatments for MS needed to control the immune response and repair the damage caused to the fatty myelin sheaths that protect the nerves.

"We've already shown that adult stem cells have great potential to both control the immune response and promote repair of the central nervous system. It also prevents further damage," Prof McColl said.

"But the trick is getting the stem cells to the right location where they can perform this function."

MS is a progressive disease in which the body attacks the central nervous system, causing nerve inflammation and scarring. It results in the impairment of motor, sensory and cognitive function. When stem cells are injected into theblood system, very few cross the blood/brain barrier into the central nervous system.

Lead investigator Dr Iain Comerford said it was hoped the manipulated adult stem cells could cross that barrier, targeting the inflammation site and repairing the damaged myelin.

"It involves promoting stem-cell migration to the central nervous system by manipulating receptors on the surface of the stem cells that control cell movement," Dr Comerford said.

"We are also modifying the stem cells to suppress the immune response by introducing molecules that regulate inflammation," Dr Comerford added.

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Multiple sclerosis hope 'lie in stem cells'

Led by Dr. Peiyee Lee and Dr. Richard Gatti, researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have used induced pluripotent stem (iPS) cells to advance disease-in-a-dish modeling of a rare genetic disorder, ataxia telangiectasia (A-T).

Their discovery shows the positive effects of drugs that may lead to effective new treatments for the neurodegenerative disease. iPS cells are made from patients' skin cells, rather than from embryos, and they can become any type of cells, including brain cells, in the laboratory. The study appears online ahead of print in the journal Nature Communications.

People with A-T begin life with neurological deficits that become devastating through progressive loss of function in a part of the brain called the cerebellum, which leads to severe difficulty with movement and coordination. A-T patients also suffer frequent infections due to their weakened immune systems and have an increased risk for cancer. The disease is caused by lost function in a gene, ATM, that normally repairs damaged DNA in the cells and preserves normal function.

Developing a human neural cell model to understand A-T's neurodegenerative process and create a platform for testing new treatments was critical because the disease presents differently in humans and laboratory animals. Scientists commonly use mouse models to study A-T, but mice with the disease do not experience the more debilitating effects that humans do. In mice with A-T, the cerebellum appears normal and they do not exhibit the obvious degeneration seen in the human brain.

Lee and colleagues used iPS cell-derived neural cells developed from skin cells of A-T patients with a specific type of genetic mutation to create a disease-in-a-dish model. In the laboratory, researchers were able to model the characteristics of A-T, such as the cell's lack of ATM protein and its inability to repair DNA damage. The model also allowed the researchers to identify potential new therapeutic drugs, called small molecule read-through (SMRT) compounds, that increase ATM protein activity and improve the model cells' ability to repair damaged DNA.

"A-T patients with no ATM activity have severe disease but patients with some ATM activity do much better," Lee said. "This makes our discovery promising, because even a small increase in the ATM activity induced by the SMRT drug can potentially translate to positive effects for patients, slowing disease progression and hopefully improving their quality of life."

These studies suggest that SMRT compounds may have positive effects on all other cell types in the body, potentially improving A-T patients' immune function and decreasing their susceptibility to cancer.

Additionally, the patient-specific iPS cell-derived neural cells in this study combined with the SMRT compounds can be an invaluable tool for understanding the development and progression of A-T. This iPS cell-neural cell A-T disease model also can be a platform to identify more potent SMRT drugs. The SMRT drugs identified using this model can potentially be applied to most other genetic diseases with the same type of mutations.

This research was supported by training and research grants from the California Institute of Regenerative Medicine, the National Institutes of Health, APRAT, A-T Ease and Scott Richards Foundation.

The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA's stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA's Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

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Stem cells show promise for treating rare nerve disease

Recently, doctors in Illinois implanted a windpipe into a 2-year-old girl.

Hanna Warren's new trachea is made of plastic fibers and her own stem cells.

Stem cells are cells that have the potential to develop into some or many different cell types in the body.

They usually serve as a repair system.

Theoretically, they can also divide without limit to replenish other cells for as long as the person or animal is still alive.

When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell - muscle cell, red blood cell, brain cell, etc.

Stem cells have potential in many different areas of health and medical research.

They help scientists understand how cells transform into the many different types of cells needed to live.

Some of the most serious medical conditions, such as cancer and birth defects, are due to problems that occur somewhere in this transforming process.

There are several sources of stem cells.

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Priority Health: Stem Cells