Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy

作者：Caroline J. Woo, Verena Maier, Roshni Davey, James F. Brennan, Guangde Li, John Brothers, Brian E. Schwartz, Susana Gordo, Anne Kasper, Trevor R. Okamoto, Hans E. Johansson, Berhan Mandefro, Dhruv Sareen, Peter Bialek, B. Nelson Chau, Balkrishen Bhat, David A. Bullough, James Barsoum · 发表于：Proceedings of the National Academy of Sciences · 年份：2017 · DOI：10.1073/pnas.1616521114 · 被引用次数：83 · 研究领域：Neurogenetic and Muscular Disorders Research、RNA modifications and cancer、RNA Research and Splicing

Significance Autosomal recessive mutations or deletions of the gene Survival Motor Neuron 1 ( SMN1 ) cause spinal muscular atrophy, a neurodegenerative disorder. Transcriptional up-regulation of a nearly identical gene, SMN2 , can functionally compensate for the loss of SMN1 , resulting in increased SMN protein to ameliorate the disease severity. Here we demonstrate that the repressed state of SMN2 is reversible by interrupting the recruitment of a repressive epigenetic complex in disease-relevant cell types. Using chemically modified oligonucleotides to bind at a site of interaction on a long noncoding RNA that recruits the repressive complex, SMN2 is epigenetically altered to create a transcriptionally permissive state.