The production, or differentiation, of such a sophisticated tissue requires an immense amount of coordination at the cellular level, and glitches in the process can have disastrous consequences. Now, researchers at the Stanford University School of Medicine have identified a master regulator of this differentiation process.
"Disorders of epidermal differentiation, from skin cancer to eczema, will affect roughly one-half of Americans at some point in their lifetimes," said Paul Khavari, MD, PhD. "Understanding how this differentiation occurs has enormous implications, not just for the treatment of disease, but also for studies of tissue regeneration and even stem cell science." Khavari is the Carl J. Herzog Professor and chair of the Department of Dermatology.
Khavari and his colleagues have found that, like a traffic cop motioning cars to specific parking spaces in a large, busy lot, a newly identified molecule called TINCR is required to direct precursor cells down pathways toward particular developmental fates. It does so by binding to and stabilizing differentiation-specific genetic messages called messenger RNAs. Blocking TINCR activity, the researchers found, stopped the differentiation of all epidermal cells.
"This is an entirely unique mechanism, which sheds light on a previously invisible portion of the regulation of this process," said Khavari, who is also a member of the Stanford Cancer Institute and chief of the dermatology service at the Veterans Affairs Palo Alto Health Care System. He is the senior author of the research, which will be published online Dec. 2 in Nature. Former Stanford postdoctoral scholar Markus Kretz, PhD, is the first author. Kretz is now an assistant professor of biology at the University of Regensburg in Germany.
Surprisingly, this coordinator extraordinaire is not a protein. (Proteins have traditionally been thought to be the primary movers and shakers in a cell, although that view is now changing somewhat.) Instead, it belongs to a relatively new, and increasingly influential, class of regulatory molecules called long, non-coding RNAs, or lncRNAs. These molecules are so named because they do not carry instructions to make proteins. They are also longer than other regulatory RNAs known as microRNAs.
But even among lncRNAs, TINCR, and its role in epidermal differentiation, is unique.
"This work revealed a new role for regulatory RNAs in gene activation — by stabilizing select messenger RNA transcripts," said co-author Howard Chang, MD, PhD, professor of dermatology. "This finding highlights the ability of regulatory RNAs to fine-tune gene expression."
The researchers identified the molecule by looking for RNAs that are more highly expressed in differentiating epidermal cells called keratinocytes than in progenitor cells. They found that levels of TINCR (short for "terminal differentiation-induced non-coding RNA") expression were 150 times greater in the keratinocytes. But to figure out what TINCR was doing, they had to develop two new assays: one to help researchers identify interactions between RNA molecules, and another to suss out interactions between a regulatory RNA and its protein partners. Such techniques will become increasingly important as researchers continue to identify the critical regulatory roles played by RNA molecules.
"These long, non-coding RNAs don't have recognizable, classic motifs like proteins do," said Khavari. "And yet, we really need to know with what other molecules they may be physically interacting to truly understand their biological roles."
The first approach, which the researchers termed RIA-Seq, couples an RNA interaction assay with a deep-sequencing technique to identify RNA partners of TINCR. Using RIA-Seq, the researchers found that TINCR and its RNA partners — many of which encode instructions for proteins essential to the differentiation process — share a common, short sequence that mediates their binding.
"These conserved, complementary motifs may help TINCR pair up with and stabilize its partner messenger RNAs," said Khavari. "In this way, TINCR may serve as a scaffold for many mRNAs involved in epidermal differentiation."
The second approach used a grid, or microarray, of 9,400 human proteins to which the researchers exposed TINCR. One of the proteins, termed STAU1, bound strongly to TINCR. STAU1 had not previously been implicated in epidermal differentiation, but the researchers found that blocking its activity prevented differentiation in a manner similar to blocking TINCR.
"This effect is quite specific for epidermal tissue," said Khavari, "and it suggests that nature has evolved a simple mechanism to control the tissue-specific expression of a large number of genes. We'd like to understand more about this TINCR-STAU1 complex to get a better idea of how it acts at a biochemical level."
In addition to identifying a unique role for a new lncRNA in epidermal differentiation, Khavari and Chang said they are excited to have developed new tools to understand how these regulatory RNAs function in the cells. "This really helps substantially expand our tool kit that we can use to analyze how RNAs and proteins interact," said Khavari.
Other Stanford researchers involved in the study include senior scientists Zurab Siprashvili, PhD, and Kun Qu, PhD; graduate students Ci Chu, Dan Webster, Ashley Zehnder, Ryan Flynn, Abigail Groff, Grace Kim and Jennifer Chow; and postdoctoral scholars Carolyn Lee, MD, PhD, Ross Flockhart, PhD, Robert Spitale, PhD, and Grace Zheng, PhD.
The research was supported by the National Institutes of Health, the California Institute for Regenerative Medicine and the U.S. Veterans Affairs Office of Research and Development.
Information about Stanford's Department of Dermatology, which also supported the work, is available at http://dermatology.stanford.edu.
The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.
Krista Conger | EurekAlert!
Penn study identifies viral product that promotes immune defense against RSV
04.09.2015 | University of Pennsylvania
Columbia Engineering team develops targeted drug delivery to lung
03.09.2015 | Columbia University School of Engineering and Applied Science
In a survey of NASA's Hubble Space Telescope images of 2,753 young, blue star clusters in the neighboring Andromeda galaxy (M31), astronomers have found that M31 and our own galaxy have a similar percentage of newborn stars based on mass.
By nailing down what percentage of stars have a particular mass within a cluster, or the Initial Mass Function (IMF), scientists can better interpret the light...
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE have developed a highly compact and efficient inverter for use in uninterruptible power...
China's Loess Plateau was formed by wind alternately depositing dust or removing dust over the last 2.6 million years, according to a new report from University of Arizona geoscientists. The study is the first to explain how the steep-fronted plateau formed.
China's Loess Plateau was formed by wind alternately depositing dust or removing dust over the last 2.6 million years, according to a new report from...
The leaves of the lotus flower, and other natural surfaces that repel water and dirt, have been the model for many types of engineered liquid-repelling surfaces. As slippery as these surfaces are, however, tiny water droplets still stick to them. Now, Penn State researchers have developed nano/micro-textured, highly slippery surfaces able to outperform these naturally inspired coatings, particularly when the water is a vapor or tiny droplets.
Enhancing the mobility of liquid droplets on rough surfaces could improve condensation heat transfer for power-plant heat exchangers, create more efficient...
Longer, more severe, and hotter droughts and a myriad of other threats, including diseases and more extensive and severe wildfires, are threatening to transform some of the world's temperate forests, a new study published in Science has found. Without informed management, some forests could convert to shrublands or grasslands within the coming decades.
"While we have been trying to manage for resilience of 20th century conditions, we realize now that we must prepare for transformations and attempt to ease...
03.09.2015 | Event News
20.08.2015 | Event News
20.08.2015 | Event News
04.09.2015 | Power and Electrical Engineering
04.09.2015 | Machine Engineering
04.09.2015 | Materials Sciences