Discovery and analysis of long noncoding RNAs in gene expression control and cell cycle progression

Recent advances in transcriptome analysis have revealed that a large proportion of the mammalian genome is transcribed. Thousands of these transcripts are classified as long non-coding RNAs (lncRNAs), with size larger than 200 nucleotides, but very few have been functionally characterized. Here, I detail a journey of the discovery and analysis of lncRNAs in gene expression control and cell cycle progression, beginning from the characterization of a mutual regulation between lncRNA MALAT1 and its natural antisense transcript TALAM1, followed by the identification and functional characterization of lncRNAs involved in cell cycle progression. The mutual regulation between MALAT1 and TALAM1 presents a novel feed-forward positive regulatory loop at the MALAT1 locus where MALAT1 positively regulates the transcription and stability of TALAM1, and TALAM1 in turn promotes the processing and maturation events of MALAT1 which are essential to maintain the high cellular levels of MALAT1. In the characterization of functional lncRNAs in cell cycle progression, I focus on an S phase-upregulated lncRNA, termed S7, and demonstrate that it plays crucial roles in cell cycle progression and tumorigenicity, through regulating the expression of genes in the cellular proliferation network including the Hippo signaling pathway. Altogether, these studies support a model whereby pervasive lncRNA transcripts, previously regarded as transcriptional byproducts, function through diverse mechanisms as critical regulators of gene expression and the vital cell cycle processes