Give me an intron: any intron

In this issue of Blood, Yuan et al provide evidence that processing of the first intronic sequence within the von Willebrand factor (vWF) gene facilitates expression by endothelial cells regardless of the source of the intron, while intron processing is irrelevant for vWF expression by megakaryocytes.¹ 

The discovery of introns in the late 1970s by Dr Phil Sharp and Sir Richard Roberts was, at the time, a surprising twist to gene organization. Expecting gene sequences to be continuous and then discovering a significant amount of transcribed DNA not present in the mature RNA transcript caused an early reference to introns as the “junk” DNA. The junk reference implied that introns were a remnant of molecular evolution with no function other than to consume energy as the cell transcribed the necessary sequences for the mature RNA.^2,3 

Some 35 years later, introns are many things, but any reference to junk DNA should be gone.⁴  The more we learn about introns, the more we can be amazed at their diverse roles. Introns can facilitate gene rearrangement, increase protein diversity, house genes within genes, and control expression at many different levels.

The gene for vWF contains 52 exons separated by 51 introns spanning almost 180 000 nucleotides.⁵  As a central component of hemostasis and thrombosis, vWF is expressed by both megakaryocytes and endothelial cells. Yet there exist examples where gene expression is altered in one cell type and not another. Is it a simple case of a single promoter with cell-specific cis elements acting independently? It’s clearly not that simple. The laboratory of William Aird has worked on the regulation of vWF gene expression and has previously reported the importance of the first vWF intron for expression in endothelial cells,⁶  but whether the intron simply contains cis-acting elements supporting endothelial-cell–specific expression or there is a basic need for processing of an intron was unknown. Now, using a series of elegant in vitro and in vivo experiments, the same group demonstrates that intronic splicing is required for endothelial-cell–specific expression of vWF (see figure). Surprisingly, introns of seemingly diverse origin, from the mouse Down syndrome critical region-1 or hagfish factor X, rescue endothelial cell expression of vWF to varying degrees in the vasculature. At the same time, megakaryocyte vWF expression is unchanged.

Yuan et al have convincingly established their conclusions with both in vitro and in vivo models. What is most surprising is that the presence of the intron did not affect messenger RNA levels but did affect protein product. What remains to be determined is whether export of the messenger RNA is influenced by processing or by an increased translational efficiency, possibly through the presence of splicing components, such as exon junction complexes, still positioned on the processed RNA.

These new findings may aid in explaining some forms of von Willebrand disease that have yet to be explained at the molecular level. As the most common hereditary bleeding disorder, the diversity of von Willebrand disease and its subgroup classification scheme can be daunting. Nevertheless, this classification is important given the range of von Willebrand disease heterogeneity, from absent vWF to nonfunctional vWF to hyperfunctional vWF. As an example, one subgroup of type 1 von Willebrand disease has reduced plasma vWF but normal levels of platelet vWF. Could aberrant vWF intronic splicing provide an explanation for this subtype of von Willebrand disease? Future studies of patient DNA samples might find mutations that reduce RNA spicing efficiency and explain the reduced plasma vWF levels found in some patients.