Since the beginning of the project, we've made substantial progress in all three aims, shining light on the mechanisms underlying the activities of several lncRNAs from each type. We studied the Silc1 lncRNA that we previously found to be induced and important during regeneration in neurons, in the context of memory formation in the hippocampus and found that without Silc1 the process of memory acquisition is significantly impaired and this occurs because the induction of Sox11, a gene found on the same chromosome as Silc1 but separated from it by ~200,000 DNA bases is lost in specific regions of the hippocampus. For another lncRNA, Meteor, we found that different elements within the gene are important for different aspects of early embryonic development, acting through the Eomes gene, which is important for the development of the heart and related tissues. To understand the second type of lncRNAs, we are mainly focused on the Chaserr lncRNA, which represses Chd2, a gene found immediately near it, on the same chromosome. Mutations in Chd2 lead to epilepsy and autism, and we are exploring targeting Chaserr as a potential treatment for Chd2 haploinsufficiency. We made substantial progress in understanding how Chaserr acts, which opens new avenues for its inhibition. In the first aim of the project, we made progress in understand the way the NORAD lncRNA folds and how this folding helps it to be very efficient in its activities, principles which we now use for the design of new potent lncRNAs.
