Master regulator of skin development

"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"

—Paul Khavari, MD, PhD Carl J. Herzog professor and chair of the department of dermatologyStanford University School of Medicine

RESEARCHERS at the Stanford University School of Medicine say they have found the molecule that is responsible for the production or differentiation of cells in the epidermis.

Photo ? Shao Chun Wang I Dreamstime.com

With other researchers, Paul Khavari, MD, PhD, a Carl J. Herzog professor and chair of the department of dermatology, has 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 stabilising differentiation-specific genetic messages called messenger RNAs. Blocking TINCR activity 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 Mr Khavari, who is the senior author of the research, published online in Nature. Former Stanford postdoctoral scholar Markus Kretz, PhD, is the first author, and is 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 amongst IncRNAs, TINCR, and its role in epidermal differentiation, is unique.

“This work revealed a new role for regulatory RNAs in gene activation – by stabilising 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 recognisable, classic motifs like proteins do,” said Mr
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.

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