Alternative splicing, a means of regulating gene expression, is involved in many biological processes including wound healing. When alternative splicing goes awry, however, various problems arise. In the case of wound healing, normal processes may surge uncontrollably, causing chronic inflammation and even promoting skin cancer.
After studying deranged wound healing at the biochemical level, a team of scientists at the Cold Spring Harbor Laboratory (CSHL) found that a protein called SRSF6, a known splicing factor, is overexpressed when ordinary healing processes slip into overdrive. SRSF6 is normally beneficial, taking part in repairing damaged skin and restoring it to a normal, or homeostatic, state. Yet when it is overproduced, SRSF6 can promote abnormal growth of skin cells and cancer.
This finding was reported January 19 in Nature Structural & Molecular Biology, in an article entitled “Splicing factor SRSF6 promotes hyperplasia of sensitized skin.” To put the finding in context, one of the article’s authors, CSHL professor Adrian Krainer, commented that “cancer resembles a state of chronic would healing, in which the wound-healing program is erroneously activated and perpetuated.”
Part of the erroneous wound healing consists of aberrant alternative splicing. In splicing, an RNA message copied from a gene is edited so that it includes only the portions needed to instruct the cell how to produce a specific protein. The messages of most genes can be edited in multiple ways, using different splicing factors; thus, a single gene can give rise to multiple proteins, with distinct functions.
When the CSHL team studied abnormal wound healing in mice, they determined the spot on a particular RNA message—one that encodes the protein tenascin C—where SRSF6 binds abnormally, giving rise to alternate versions of the tenascin C protein. In their paper, the scientists wrote, “We identify 139 SRSF6-target genes in skin and show that this SR-rich protein binds to alternative exons in the pre-mRNA of the extracellular-matrix protein tenascin C, thus promoting the expression of isoforms characteristic of invasive and metastatic cancer independently of cell type.”
The CSHL team also found that overproduction of SRSF6 in mice results in the depletion of a type of stem cell called Lgr6+. These skin stem cells reside in the upper part of the hair follicle and participate in wound healing when tissue is damaged. This result indicates that aberrant alternative splicing by SRSF6 not only increases cell proliferation, it also prevents the process by which proliferating cells mature. “The cells remain in an abnormal activation state that would otherwise be temporary during normal tissue repair,” observed Mads Jensen, Ph.D., another study author and a postdoctoral researcher in the Krainer lab.
The Krainer lab studies the posttranscriptional control of gene expression, alternative splicing, splicing in genetic diseases and cancer, and splicing-targeted antisense therapeutics. For many protein-coding genes, the lab notes, alternative splicing regulates the production of multiple isoforms. Splicing requires >200 proteins and five snRNAs that assemble into a macromolecular machine, the spliceosome. As the Krainer lab has determined, defects in the spliceosome can give rise to many genetic diseases besides skin cancer.