SMCHD1 is a target for gene activation therapy to treat Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of expression from the active paternal allele at an imprinted cluster on chromosome 15. Current treatments address individual symptoms rather than the underlying cause of disease. Because all patients preserve a normal but epigenetically silenced maternal copy of these genes, activation of this copy offers a potential disease-modifying therapy. Here, we investigated the epigenetic regulator SMCHD1. First, we demonstrated that SMCHD1 represses the PWS locus in both mice and humans, supporting its relevance as a therapeutic target. Second, we found that SMCHD1 represses the entire PWS locus in neural lineages, extending its previously known role beyond only part of the cluster. Deleting Smchd1 after early development in vivo activated PWS genes in disease-relevant mouse tissues including hypothalamus and improved phenotypes in a PWS mouse model. Despite broader genome-wide binding, postearly development targeting of SMCHD1 appeared remarkably safe, supporting its potential for gene activation therapy for PWS.