Role of long noncoding RNAs in Polycomb‐mediated gene silencing

Abstract

Recent evidence suggests that long non‐protein coding RNA (lncRNA) acts as a flexible scaffold to bind and guide the right combination of proteins to a specific genomic location to regulate gene expression. Previously, we have identified lncRNAs as key cofactors for histone methyltransferase, Polycomb Repressive Complex 2 (PRC2), in transcriptionally suppressing genes functioning in X‐inactivation. Furthermore, we discovered over 9000 PRC2 interacting RNAs in mouse embryonic stem cells (mESCs). Interestingly, highly enriched RNA peaks often locate at the 5′end non‐coding regions, including introns and 5′‐UTRs, of protein coding genes. Genes with such peaks are often highly expressed in mESCs but decrease significantly in fibroblasts, suggesting these genes are not silenced but are “poised” for silencing. This observation suggests PRC2‐RNA interaction may be important for silencing gene expression upon mESC differentiation but is not essential for maintaining mESC in an undifferentiated state. Indeed, PRC2 deficient mESCs can self‐renewal and stay undifferentiated. However, these cells cannot be differentiated into specific lineages, such as neuronal precursors. We conclude noncoding regions of a coding RNA play an essential role in PRC2‐mediated gene silencing upon mESC differentiation, providing a novel mechanism of gene regulation by noncoding elements during development.