In any given tissue, the elements that regulate gene expression may settle into a hierarchy, one determined by an element called a pioneer factor. Evidence for such a hierarchy has been found in epithelial cells, where a pioneer factor called Grainy head plays the role of master regulator by determining the accessibility of enhancer sequences.
Grainy head doesn’t activate the enhancer sequences itself. It merely exposes them to other regulatory elements that assume the activation duties. In a sense, Grainy head acts like the head librarian in an archive, separating mobile shelving units, permitting the passage of assistant librarians, who then busy themselves putting the stored information to work.
This information-accessing arrangement, with Grainy head at the top of the pyramid, was uncovered by scientists based at the Flanders Institute for Biotechnology, which is also known as VIB. Working with epithelial cells, these scientists studied how DNA sequence information, chromatin accessibility, and gene expression are linked.
The findings may be relevant to cell types other than epithelial cells. Also, the findings may open new approaches to cellular reprogramming and regenerative medicine.
Details appeared June 4 in the journal Nature Genetics, in an article entitled “The Transcription Factor Grainy Head Primes Epithelial Enhancers for Spatiotemporal Activation by Displacing Nucleosomes.” The article describes how the VIB team used a combination of computational biology and in vivo experiments to show how DNA regions relevant to epithelial cells are accessed.
“Using ATAC–seq across a panel of Drosophila inbred strains, we found that SNPs [single-nucleotide polymorphisms] affecting binding sites of the TF [transcription factor] Grainy head (Grh) causally determine the accessibility of epithelial enhancers,” wrote the articles authors. “We show that deletion and ectopic expression of Grh cause loss and gain of DNA accessibility, respectively.”
Previous research had shown that in the absence of Grainy head, developmental problems arise and wound healing is disturbed. Loss of Grainy head had also been linked to increased cancer metastasis. Explaining these observations had been tricky, as relevant genes were found to be upregulated in one instance, but downregulated in another.
These earlier findings make more sense now that Grainy head has been shown to sit at the very top of the regulatory hierarchy in epithelial cells. It essentially acts as a key that can be used to access the relevant DNA regions.
In the current study, the VIB scientists emphasized while Grh binding is necessary for enhancer accessibility, it is insufficient to activate enhancers. The scientists also indicated that human Grainy head analogs function like the fruit fly Grainy head.
“Grh binding is necessary and sufficient for the opening of epithelial enhancers but not for their activation,” the article’s authors concluded. “Our data support a model positing that complex spatiotemporal expression patterns are controlled by regulatory hierarchies in which pioneer factors, such as Grh, establish tissue-specific accessible chromatin landscapes upon which other factors can act.”
“We found that access to the DNA regions that are relevant for epithelial cells is governed by a protein called Grainy head,” said Jelle Jacobs, the first author of the current study and a researcher in the VIB lab of Stein Aerts, Ph.D. “Grainy head is necessary to 'unlock' these specific DNA regions, which in turn allows other players to move in and turn genes on or off.”
“We can now explore if we can use this lock-and-key system to open up or close off other parts of the genome in a controlled way as well,” added Aerts. “This could be helpful, for example, in regenerative medicine, to direct cells to turn on specific genetic programs for skin cells or any other type of cells.”