Noncoding DNA sequence required for epidermal differentiation

By Liam Davenport, medwireNews Reporter

The differentiation of human epidermis is controlled and stabilized by a long noncoding RNA termed terminal differentiation-induced noncoding RNA (TINCR) acting through a post-transcriptional mechanism, the results of an innovative US study indicate.

"This is an entirely unique mechanism, which sheds light on a previously invisible portion of the regulation of this process," commented lead researcher Paul Khavari (Stanford University School of Medicine, California, USA) in a press statement.

He added: "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."

Studying primary human keratinocytes isolated from freshly discarded surgical skin samples, and cultured with epidermal growth factor and bovine pituitary extract, the team found that the 3.7-kilobase TINCR was expressed in keratinocytes at a level 150-fold higher than that seen in progenitor cells.

Epidermis lacking TINCR did not have differentiated epidermis ultrastructure, such as keratohyalin granules and intact lamellar bodies. Conversely, TINCR was associated with increased levels of messenger RNA (mRNA) for key differentiation genes, some of which - for example, FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14, and ELOVL3 - are mutated in human skin diseases.

Writing in Nature, the researchers report that they used a technique known as genome-scale RNA interactome analysis to identify interactions between RNA molecules. This analysis indicated that TINCR interacts with a wide range of differentiation mRNAs via a 25-nucleotide 'TINCR box' motif that is enriched in interacting mRNAs and required for TINCR binding.

In a further experiment, the team analysed TINCR binding capacity to approximately 9400 human recombinant proteins, on a microarray. This revealed that there was direct binding between TINCR and staufen1 (STAU1) protein, which has not previously been linked to epidermal differentiation.

Tissue lacking STAU1 replicated the effect of TINCR deficiency, while lack of UPF1 and UPF2, which are required for STAU1-mediated RNA decay, did not affect differentiation, prompting the team to suggest that the TINCR-STAU1 complex mediates stabilization of mRNAs involved in differentiation.

Co-author Howard Chang, also from Stanford University, told the press: "This finding highlights the ability of regulatory RNAs to fine-tune gene expression."

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