Transcriptional repression mechanisms in controlling human embryonic stem cell pluripotency

Human stem cells promise to be one of the future cornerstones of regenerative medicine due to being able to potentially convert them into any cell type and hence replace failing systems. However, before this can be achieved we need to understand how these cells are specified and the key to this is understanding the underlying regulatory mechanisms that act to control gene expression. The ERK signalling pathway is a central regulatory pathway in human embryonic stem cells, and this impacts on gene expression through a number of transcription factors including the ETS protein ELK1. Importantly this pathway is also deregulated in tumourigenesis. Recent studies have identified ELK1 as a key transcription factor in the maintenance of embryonic stem cell pluripotency in response to ERK pathway signalling. It does this through its ability to activate transcription but also has an important regulatory role as a transcriptional repressor. However, it is unclear how ELK1 functions as a repressor in this context, and indeed how ELK1 can toggle between repressive and activating modes on different target genes. The aim of this project will be to employ molecular and genomic approaches to study how ELK1 represses transcriptional networks in the context of human embryonic stem cells.