Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients only have the switched off copies that came from the mother’s chromosome 15. My laboratory has identified a component of the switch off mechanism, a protein called ZNF274. In this proposal, we are attempting to destroy ZNF274 in stem cell lines created from PWS skin cells. We are asking if the set of genes in the maternal chromosome 15 get switched on in these ZNF274-less PWS stem cells. If so, this could lead to ways of improving the symptoms of PWS. We are also asking if the maternal genes stay on in brain cells and in so-called “mini-brains” that we generate from the stem cells. The stem cell “mini-brains” could offer a more realistic model of the PWS brain gene abnormalities. While many hurdles remain, we hope to develop approaches to turning on the genes that are switched off PWS while not affecting other important genes.