In mice, many of these genes are clustered together in chromosomal regions specific to the expression of keratin and related proteins, and in a site called the "epidermal differentiation complex." The proteins coded for by the genes in the clusters are necessary to the process of toughening, or cornifying (the word means "making horn"), the cell envelopes essential to the skin barrier. These gene assemblies are just the sort that Satb1 controls in other systems by chromatin remodeling.

Satb1 doesn't always bind to DNA close to where a gene's transcription starts, however. It typically bends and folds the chromatin to bring the right groups of genes together. Thus, when Satb1 binds to a specific site, genes as far as 200,000 base pairs away may be activated.

Two kinds of knockout mice, lacking either the p63 or the Satb1 gene, exhibited similar impacts on expression of their skin-related genes, and they had decreased amounts of the same proteins involved in cell cornifying. Both kinds of knockout mice had the thinner skins.

The effects of missing p63 on expression of many genes were so close to those of missing Satb1 as to suggest to the researchers that Satb1 plays an important function in skin development as a gene "downstream" of the p63 protein - a primary target of its activity. Indeed, a series of tests showed that p63 directly regulates the Satb1 gene.

A final test was the most suggestive of them all. If the lack of p63 causes a thin epidermis, a lack of cell growth, and a decrease in such critical proteins as loricrin (necessary to form the tough envelope of the outermost skin cells), can Satb1 reverse this degenerative process?

The researchers used a virus to transport the Satb1 gene into samples of skin from p63 knockout mice. The result was a significant increase in epidermal thickness, cell proliferation, and loricrin levels. The research team concluded that Satb1 is capable of partially restoring the normal epidermis in p63-deficient mice.

Says Kohwi-Shigematsu, "Our collaboration on skin development with Botchkarev's lab, which made the major contribution to this study, and our other colleagues was exciting because we learned both a new key player and a novel strategy that cells use to make skin: the master regulator p63 uses Satb1's skills to do much of its work."

Knowledge of how these essential genes and proteins work together holds promise for better understanding and eventual progress in addressing a wide range of skin disorders.

Source: DOE/Lawrence Berkeley National Laboratory