Small RNA molecules such as exogenously introduced small RNA and naturally occurring miRNA have been mainly found to function in the cytoplasm to silence gene expression at the post-transcriptional level by targeting homologous sequences, a phenomenon known as RNA interference (RNAi). However, the nuclear function of small RNA in mammalian cells is largely unknown. The overall research theme of my laboratory is to understand how small RNAs function in the nucleus of mammalian cells to regulate gene transcription and epigenetic memory, and the potential implications of such regulatory mechanisms in normal cells and diseased cells such as cancer cells. Our seminal work on the identification of RNA activation (RNAa) demonstrates that promoter-targeted small RNAs are able to activate gene expression through a nuclear mechanism that is distinct from RNAi. Ongoing research in the laboratory focuses on (1) understanding the molecular mechanism of RNAa by using a combination of genomic, bioinformatic, and molecular biology approaches, (2) identifying the interactions of small RNA with the genome and analyzing their functional roles in normal cellular processes and in cancer development at a genome-wide scale, (3) exploiting the RNAa mechanism for the treatment of diseases, such as cancer, through targeted activation of disease-related genes, and (4) for cell fate reprogramming.