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Breakthrough in how stem cells become specialized

Scientists have made a major advance in understanding how cells, each containing all the same genetic information, become diverse. It seems the OCT4 protein primes specific genes to begin differentiation.

Each stem cell contains all the same genetic information, yet become uniquely diverse as various tissues of the body. Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) in Florida, may have the answer.

Their study published in Molecular Cell shows that a protein called OCT4 narrows the range of cell types that stem cells, undifferentiated cells, can become. This information could impact efforts to develop therapies to treat diseases by reproducing specific cells, as well as better understand which cells are affected by drugs that influence cell specialization.

"We found that the stem cell-specific protein OCT4, primes certain genes that, when activated, cause the cell to differentiate or become more specialized. This priming customizes stem cells' responses to signals that induce differentiation and makes the underlying genetic process more efficient."

Laszlo Nagy MD PhD, Professor and Director, Genomic Control of Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Florida, USA and senior author of the study.

Differentiation matters as an organism develops from its earliest cells to form into a highly flexible state — stem cells — to more specialized cell types that make up its tissues. Many labs are trying to recapitulate this process. Their goal is to generate specific cell types that could be transplanted into patients to treat disease and injury. For example, pancreatic beta cells could treat diabetes, and neurons that produce dopamine could treat Parkinson's.

OCT4 is a transcription factor — a protein that regulates gene activity. It maintains a stem cells' ability to give rise to any tissue in the body. OCT4 works by sitting on DNA where it recruits other factors in the cell to either help initiate, or repress the reading of, specific genes.

The study shows how OCT4 collaborates with certain genes to activate external signals — such as RAR (vitamin A or retinoic acid), and beta-catenin (which regulates cell to cell adhesion) — to turn on specific genes.

Vitamin A converts stem cells into neuronal precursor cells — cells that specialize in impulse conduction. Activation of beta-catenin by Wnt can either support pluripotency (continue to be capable of giving rise to several different cell types) or in combination with other cells signals, promote non-neural differentiation. Wnt signaling is involved in virtually every aspect of embryo development and controls internal stability in a number of adult tissues.

Recruitment of these factors 'primes' a subset of genes to identify and measure available genes to be activated.

Nagy continues: "Our findings suggest a general principle for how the same differentiation signal induces distinct transitions into various types of cells. Whereas in stem cells, OCT4 recruits RAR to neuronal genes, in bone marrow cells another transcription factor would recruit RAR to become genes for the granulocyte [white blood cell] program.

"Which factors determine the effects of differentiation signals in bone marrow cells and other cell types, is still to be determined.
In a sense, we've found the code for stem cells that links the input -- signals like vitamin A and Wnt — to output — a new cell type. Now we plan to explore whether other transcription factors behave similarly to OCT4. That is, we plan to find the code for more mature cell types. If other factors also have this dual function: both maintaining the current state and priming certain genes to respond to external signals, that would answer a key question in developmental biology and advance the field of stem cell research."

•OCT4 occupies differentiation-related and low-accessible genomic regions in ESCs
•OCT4 positively controls the level of RARγ
•Loss of OCT4 causes dysregulation of tissue-specific RA and WNT/β-catenin response
•Overexpression of OCT4 is sufficient to reprogram a cell type-specific signal response

Cell type specification relies on the capacity of undifferentiated cells to properly respond to specific differentiation-inducing signals. Using genomic approaches along with loss- and gain-of-function genetic models, we identified OCT4-dependent mechanisms that provide embryonic stem cells with the means to customize their response to external cues. OCT4 binds a large set of low-accessible genomic regions. At these sites, OCT4 is required for proper enhancer and gene activation by recruiting co-regulators and RAR:RXR or β-catenin, suggesting an unexpected collaboration between the lineage-determining transcription factor and these differentiation-initiating, signal-dependent transcription factors. As a proof of concept, we demonstrate that overexpression of OCT4 in a kidney cell line is sufficient for signal-dependent activation of otherwise unresponsive genes in these cells. Our results uncover OCT4 as an integral and necessary component of signal-regulated transcriptional processes required for tissue-specific responses.

This research was performed in collaboration with scientists at the University of Debrecen in Hungary, the University of Leicester in the United Kingdom, the Max Planck Institute for Molecular Genetics, the University of Würzburg and the Max Delbrück Center for Molecular Medicine in Germany, the Institut de Génomique in France, and Weill Cornell Medical College, and supported by grants from the Hungarian Scientific Research Fund, the Hungarian Brain Research Program, and the U.S. National Institutes of Health.

About SBP
Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

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A stem cell can



Phospholid by Wikipedia National Academy of Sciences online book of Understanding Stem Cells