The surface of your skin, called the epidermis, is a complex mixture of many different cell types — each with a very specific job. 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.
Stanford University Medical Center: http://med-www.stanford.edu/MedCenter/MedSchool
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
After a severe brain injury, some people remain in a vegetative or minimally conscious state, unable to speak or move intentionally, and apparently unaware of the world around them. But in recent years, neuroscientists have found signs that some of these patients may still be conscious, at least to a degree. Now researchers have used a branch of mathematics called graph theory to search for neural signatures of consciousness.
Few parasitoids are more bizarre or disturbing than the wasps of the genus Glyptapanteles, whose females inject their eggs into living caterpillars. Once inside, the larvae mature, feeding on the caterpillar’s body fluids before gnawing through its skin en masse and emerging into the light of day. And despite the trauma, not only does the caterpillar survive---initially at least---but the larvae proceed to mind-control it, turning their host into a bodyguard that protects them as they spin their cocoons and finish maturing. Then, finally, the caterpillar starves to death, but only after the tiny wasps emerge from their cocoons and fly away.
From their new book A History of Life in 100 Fossils, Paul Taylor and Aaron O'Dea share the story of 10 incredible fossils
We love origin stories. When we see successful groups of animals and plants, we wonder where they came …
First research of its kind shows that tasers could impair a person's memory and thought process
Sometimes the most fascinating animals are the ones that are no longer with us. The oddly named sthenurine is no exception.
Australian banded stilts use mysterious cues to know when to head toward ephemeral lakes in the country’s otherwise dry interior
The intriguing story of how whale evolution was unpicked is told in The Walking Whales, revealing what it's like to be a globe-trotting palaeontologist
Cells derived from embryos appear to have improved vision in more than half of the 18 patients who had become legally blind because of two progressive, currently incurable eye diseases.
Oil rigs are rarely lauded by conservationists, but fish seem to love them – they have more fish living around them than natural rocky reefs do