At the genetic level, Prader-Willi syndrome (PWS) is due to the lack of expression of a specific portion of chromosome 15. This portion contains genes that, in normal circumstances, are only active on the paternally inherited chromosome. Indeed, the corresponding genes on the maternally inherited chromosome are silenced â€“ a phenomenon called imprinting. Most frequently, Prader-Willi patients have either physically lost DNA sequences on paternal chromosome 15, which results in the deletion of the normally active paternal genes, or have inherited two copies of the maternal chromosome, which is silent. In rare cases, Prader-Willi patients have received normal chromosomes from their parents but for an unknown reason, the paternal portion is silent. While rarer, these events are nonetheless important since they are thought to correspond to a defect in the imprinting process itself. Here, we propose to focus our efforts on a critical region of chromosome 15 that allows the paternal chromosome to resist silencing and therefore to remain active. Based on a significant amount of preliminary data, we describe a novel feature of this region that, we believe, contributes to protect the paternal chromosome 15 from the action of widespread silencing complexes in our cells. Our proposal offers to further characterize this novel feature and to demonstrate that it functions by setting in place two independent and complementary mechanisms allowing the paternal chromosome to resist silencing. This work will represent an important advance in our understanding of the imprinting mechanism and will offer new clues as to why silencing sometimes occurs on the paternal chromosome, leading to PWS. A deeper understanding of the mechanism of imprinting might also lead to new treatment avenues for PWS.