The Hippo Pathway Effectors TAZ/YAP Regulate Dicer Expression and miRNA Biogenesis Through Let-7 [RNA]

December 9th, 2013 by Chaulk, S. G., Lattanzi, V. J., Hiemer, S. E., Fahlman, R. P., Varelas, X.

MicroRNAs (miRNAs) are genome encoded small double stranded RNAs that have emerged as key regulators of gene expression, and are implicated in most aspects of human development and disease. Canonical miRNA biogenesis involves processing of ~70 nucleotide pre-miRNA hairpins by Dicer to generate mature ~22 nucleotide miRNAs, which target complementary RNA sequences. Despite the importance of miRNA biogenesis, signaling mechanisms controlling this process are poorly defined. Here we demonstrate that the post-transcriptional regulation of Dicer is controlled by the cell density-mediated localization of the Hippo pathway effectors TAZ and YAP (TAZ/YAP). We show that nuclear TAZ/YAP, which are abundant at low cell density, are required for efficient pre-miRNA processing. Knockdown of TAZ/YAP in low-density cells, or density-mediated sequestration of TAZ/YAP into the cytoplasm, results in the defective processing of pre-miRNAs. Strikingly, one exception is Let-7, which accumulates upon loss of nuclear TAZ/YAP, leading to Let-7-dependent reduction in Dicer levels. Accordingly, inhibition of Let-7 rescues the miRNA biogenesis defects observed following TAZ/YAP knockdown. Thus, density-regulated TAZ/YAP localization defines a critical and previously unrecognized mechanism by which cells relay cell contact-induced cues to control miRNA biogenesis.