Master regulator of skin development discovered
Researchers at the Stanford University School of Medicine have identified a molecule that regulates the differentiation of all epidermal cells.
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, the Stanford researchers 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. 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," said Paul Khavari, who 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.
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. This finding highlights the ability of regulatory RNAs to fine-tune gene expression," said co-author Howard Chang, MD, PhD, professor of dermatology.
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.
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.
The findings has been published online Dec. 2 in Nature.