Many splicing factors that dictate splicing decisions in cells have been recently identified as important regulators of pluripotency and differentiation. In pluripotent cells and during development, regulated splicing may be particularly important because it allows for fine-tuning and plasticity of gene expression. Splicing regulators have also been implicated as a primary cause for a number of genetic diseases, and their expression is frequently mis-regulated in cancer. Importantly, there are significant similarities between the gene regulatory networks of self-renewing, immortal stem cells and transformed, immortal cancer cells.
SR proteins are a conserved family of splicing factors essential for pre-mRNA splicing and cell survival. Our previous research has shown that SR proteins regulate functionally related sets of genes that depend on cell type. We have also discovered that SR proteins are multifunctional regulators of gene expression that can impact the gene expression output of cells by several mechanisms during multiple steps of gene expression. Intriguingly, SRSF3 cross-regulates the expression of other SR proteins and other regulators of splicing and transcription, implying that it may act as a “master regulator” of gene expression programs.
Our recent results indicate that SR proteins may play an important role in the regulation of stem cell properties. SR protein family members are able to transform cells and our recent findings implicate them in the control of proliferation of stem cells. A similar pro-proliferative response has been observed in cancer cells where SR proteins are often expressed at elevated levels. Using mouse models we are currently investigating the gene regulatory networks controlled by SR proteins that confer the proliferative advantage. We are also studying the role of SR proteins in the re-entry of somatic cells into the cell cycle using both cancer-susceptible mice and induced pluripotent stem cells as models.