Project Summary The Chang lab has pioneered discoveries of long noncoding RNAs (lncRNAs) as a pervasive and important class of regulators in human diseases, notably in cancer. LncRNAs can serve as the interface between DNA and chromatin modification machinery, and thus mediate epigenetic aberrations in cancer. The lncRNA HOTAIR is overexpressed in approximately a third of human breast carcinomas and is a powerful predictor of eventual metastasis and death. The long term goal of this program is to understand the mechanistic basis of lncRNA action in human cancers. Our investigations will address (i) the roles of lncRNAs in driving cell-to-to cell epigenetic heterogeneity, a critical issue in cancer metastasis and therapy resistance, using cutting edge single cell epigenomic technology and in vivo genetic models; (ii) the emerging roles of RNA chemical modifications in cancer development; (iii) noncoding mutations that change RNA structure (“ribosnitches”) and use new epigenome editing technologies to pinpoint driver lncRNA genes in human cancers. These experiments will provide key insights into how long noncoding RNAs may instigate cancer progression, and should pave the way for new cancer diagnostics and treatments in the future.