The long noncoding RNA SPRIGHTLY (SPRY4-IT1): a new player in different diseases
Long noncoding RNAs (lncRNAs) were once dismissed as non-functional genomic noise. There is now compelling evidence that lncRNAs play critical roles in human pathophysiology. However, the molecular mechanisms by which the vast majority of lncRNAs regulate their target genes, and proteins remain unclear. The goal of this project is to characterize the molecular mechanisms and regulatory functions of a critical lncRNA, SPRIGHTLY, which is known to participate in human diseases and cancer development. We and others have previously reported that SPRIGHTLY (formally called SPRY4-IT1) is transcribed from the first intron of the SPRY4 gene and is downregulated in normal human melanocytes but highly upregulated in human melanomas and other cancers. By determining SPRIGHTLY’s 3D structure by SHAPE-seq and using this structure to probe interacting RNA molecules by pull-down experiments, we have identified six cancer-related pre-mRNAs that preferentially bind to SPRIGHTLY. Hemizygous knockout (using CRISPR) of SPRIGHTLY in melanoma cells significantly decreases SPRIGHTLY lncRNA levels and simultaneously the levels of its interacting pre-mRNA molecules, decreases anchorage-independent growth, and reduces in vivo tumor growth in mouse xenografts. This is the first demonstration of a lncRNA’s 3D coordinating role in cancer-related gene expression, but how SPRIGHTLY regulates target pre-mRNA expression from genetically unlinked loci at the genomic and epigenomic levels is unknown. We will discuss the therapeutic and biomarker potential of SPRIGHTLY and our studies should provide novel and general insights into how lncRNAs regulate cellular states through their interactions with target molecules in human cancers.
Sanford Burnham Medical Discovery Institute & The Johns Hopkins University
Domain 1 - UMR 3347 / U1021 - Normal and pathological signaling