Our major goal is to understand how lncRNAs interact with chromatin complexes to achieve locus-specific and temporally specific gene expression patterns. We use X-chromosome inactivation (XCI) as a model to study the structure and function of long noncoding RNAs (lncRNA) in epigenetic regulation, and then extend our findings to networks of RNA-protein interactions on a genome-wide scale. Nowhere in the mammalian genome are the abundance and roles of lncRNA more evident than at the X-inactivation center (Xic). This region harbors transcripts that serve as both repressors and activators in the regulation of genes on the X-chromosome. Interestingly, until 150 million years ago, the Xic genes were actually coding and functioned in pathways unrelated to XCI. The replacement of the Xic with noncoding transcripts suggests that lncRNAs may be uniquely suited to some types of epigenetic processes. Our research indicates that two such processes are allelic (cis-regulatory) and locus-specific targeting of chromatin factors (e.g., Polycomb complexes). In addition to pursuing mechanisms of action at the Xic, we are extending analysis to lncRNA occurring on a genome-wide scale and developing novel molecular techniques to do so. We have shown that lncRNAs play a critical role, not only in normal embryonic development, but also in the development of diseases such as cancer. Thus, a major concurrent goal is to leverage the functions of lncRNA to modulate gene expression towards therapeutic purposes. We are especially interested in epigenetic diseases such as Rett Syndrome and cancer.