Year 3

To gain insights into the importance of RNA regulation in embryonic stem cell self-renewal and pluripotency, we have chosen to study the RNA binding protein LIN28, one of the key genes important in stem cell biology as well as a factor in reprogramming somatic cells into induced pluripotent stem cells. In addition, the LIN28 gene is important in cancer (usually highly expressed), diabetes and obesity. Most of its role in biology has been thought to occur through the microRNA let-7. In this award period, we completed our objective to identify other RNA targets of LIN28. In doing so we have performed a genome-wide nucleotide-level resolution map of LIN28 binding sites in messenger RNAs in human embryonic stem cells and somatic cells expressed a tagged version of LIN28. Surprisingly, we find that LIN28 binds to these mRNAs and changes the expression levels of splicing factors (other RNA binding proteins) – which results in alternative splicing changes in a large network of genes. Furthermore LIN28 also regulates itself. Our results suggest novel mechanisms of gene regulation by LIN28 independent of the let-7 microRNA. We have published this in the journal Molecular Cell