Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Dimmer Switch for Regulating Cell's Read of DNA Code

11.01.2013
Epigenetics - the science of how gene activity can be altered without changes in the genetic code - plays a critical role in every aspect of life, from the differentiation of stem cells to the regulation of metabolism and growth of cancer cells.

Epigenetic factors act by reworking the structure in which genes reside, called chromatin. Inside chromatin, DNA is wound around proteins called histones. Several new cancer treatments interfere with the function of enzymes that chemically mark the histones to alter the readout of the DNA code and ramp the expression of genes up or down, as if with a dimmer switch. Enzymes called histone deacetylases (HDACs) erase the mark and shut off gene expression.

A team led by Mitchell A. Lazar, M.D., Ph.D., director of the Institute for Diabetes, Obesity, and Metabolism at the Perelman School of Medicine, University of Pennsylvania, has been studying HDAC3 for several years. They discovered that the enzyme activity of HDAC3 requires interaction with a specific region on another protein, which they dubbed the Deacetylase Activating Domain or "DAD.” This “nuts and bolts” discovery on the epigenetic control of a person’s genome has implications for cancer and neurological treatments.

This domain is found only in proteins that are nuclear receptor corepressors (NCoR1 and NCOR2), which assist receptor proteins in the nucleus to downregulate gene expression.

The team showed that HDAC3 enzyme activity is undetectable in mice bearing mutations in the DAD of both NCOR1 and NCOR2, also called SMRT, despite having normal levels of HDAC3 protein. The findings were published this week in Nature Structural & Molecular Biology.

HDAC3 is required for normal mouse development and tissue-specific functions. In cell culture studies, the HDAC3 protein itself has minimal enzyme activity but gains its histone-deacetylation function from stable association with the DAD.

“We developed a unique mouse model to directly test whether HDAC3 absolutely requires NCOR1 and/or SMRT to be activated,” says Lazar. “The answer is yes.” The results clearly show that, although tissue levels of HDAC3 are normal in this mouse model, the protein does not have detectable enzyme activity in embryos and various tissues of the engineered mice.

Surprisingly, the engineered mice are born and live to adulthood, whereas genetic absence of HDAC3 is lethal to the mice before they are born. This suggests that HDAC3 may have a deacetylase-independent function which, Lazar says, “is potentially of major importance, because HDAC inhibitors are currently used clinically to treat cancer, and are in clinical development for neurological illnesses and other disorders. We are working hard in the lab to sort this out.”

Co-authors are Seo-Hee You, Hee-Woong Lim, Zheng Sun, Molly Broache, and Kyoung-Jae Won, all from Penn. The research was supported in part by the National Institute of Diabetes, and Digestive and Kidney Diseases (R37DK43806) and a Mentor Based Fellowship from the American Diabetes Association.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

Karen Kreeger | Newswise
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht Molecular microscopy illuminates molecular motor motion
26.07.2017 | Penn State

nachricht New virus discovered in migratory bird in Rio Grande do Sul, Brazil
26.07.2017 | Fundação de Amparo à Pesquisa do Estado de São Paulo

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Carbon Nanotubes Turn Electrical Current into Light-emitting Quasi-particles

Strong light-matter coupling in these semiconducting tubes may hold the key to electrically pumped lasers

Light-matter quasi-particles can be generated electrically in semiconducting carbon nanotubes. Material scientists and physicists from Heidelberg University...

Im Focus: Flexible proximity sensor creates smart surfaces

Fraunhofer IPA has developed a proximity sensor made from silicone and carbon nanotubes (CNT) which detects objects and determines their position. The materials and printing process used mean that the sensor is extremely flexible, economical and can be used for large surfaces. Industry and research partners can use and further develop this innovation straight away.

At first glance, the proximity sensor appears to be nothing special: a thin, elastic layer of silicone onto which black square surfaces are printed, but these...

Im Focus: 3-D scanning with water

3-D shape acquisition using water displacement as the shape sensor for the reconstruction of complex objects

A global team of computer scientists and engineers have developed an innovative technique that more completely reconstructs challenging 3D objects. An ancient...

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

 
Latest News

CCNY physicists master unexplored electron property

26.07.2017 | Physics and Astronomy

Molecular microscopy illuminates molecular motor motion

26.07.2017 | Life Sciences

Large-Mouthed Fish Was Top Predator After Mass Extinction

26.07.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>