The role of microRNA in regulation of lineage-specific gene expression through the cell cycle

The establishment and maintenance of highly specialised cell lineages is fundamental to the development of multicellular organisms. Cell identity is determined by specific transcriptional profiles, which are mediated by sequence-specific, chromatin-based and post-transcriptional mechanisms of gene regulation. Changes in cell morphology and chromatin structure which occur during the cell cycle present a challenge to the maintenance of lineage-specific gene expression profiles. This study investigates the role of post-transcriptional regulation by microRNAs in stabilising cell-specific gene expression through the process of cell growth and division. Data presented here show that microRNAs are inherited through mitosis in mammalian cells, and are capable of regulating target gene expression in recipient daughter cells. Genome-wide expression analysis indicates that key developmentally regulated genes marked by a bivalent chromatin signature are globally upregulated in microRNA-deficient ES cells. Binding sites for ES cell-specific microRNAs are significantly enriched in the 3'UTR of these transcripts compared to the rest of the transcriptome, strongly suggesting that microRNAs contribute to maintenance of ES cell identity by co-ordinately regulating multiple lineage inappropriate genes. Finally, analysis of the expression of validated microRNA targets and bivalent genes throughout the cell cycle shows that transcripts from these genes accumulate in G2/M to a greater extent in microRNA-deficient ES cells than in wildtype cells. Taken together, data presented in this study support a role for microRNAs in regulation of lineage-specific gene expression through the cell cycle.