The link between RNA binding proteins and development
We are interested in alternative RNA processing in development. We specifically have been focussing on a group of interacting nuclear RNA binding proteins. Although we started to work on germ cells by looking at RBMY, this protein complex likely exists in all tissues, but has different component proteins. These proteins fall into 4 groups. The RBM group contains RBMY which is a gene deleted from the Y chromosome in some infertile men, and also contains an X-linked homologue RBMX and a retrotransposed copy HNRNPGT. The STAR group contains SAM68 and T-STAR which are proteins involved in Signal Transduction and RNA processing. The Scaffold Attachment Factors contain SAFB1 and SAFB2, which are estrogen receptor co-repressors and might have a role in breast cancer. The SR proteins and tra2β, which are important splicing regulators. Because all of these proteins are splicing regulators, our hypothesis is that these will be regulating alternative splicing which is very important in development.
We recently identified a new testis specific splice in the HIPK3 transcript called HIPK3T which is induced by tra2β and repressed by hnRNPA1. The proteins encoded by these two spliced isoforms localise differently in the nucleus: both are nuclear, but full length HIPK3 goes to PML bodies. We have done a lot of protein interaction screening to identify new interacting proteins which might be part of this complex. Using this approach we found that the E3 ubiquitin ligase SIAH1 regulates the protein stability of T-STAR, and together with Professor Keith Jones of the Institute for Cell and Molecular Biosciences we are investigating new targets for the SIAH1 protein. We found that this regulation evolved in the primate lineage, and so regulation of this protein may be important in controlling alternative splices which contribute to the specific development of the human brain.
We are using a combination of cell and molecular biology, coupled to mouse models to investigate this protein complex in different cell types and tissues.
Ingrid Ehrmann BSc PhD
BBSRC Senior Research Associate
Caroline Dalgliesh BSc
Wellcome Trust Research Assistant
Sushma Nagaraj Grellscheid BSc MSc PhD
Wellcome Trust Research Associate
Association of International Cancer Research Research Assistant
Marie Maclennan BSc MSc
BBSRC PhD student