Transcriptional regulation of miR-30a by YAP impacts PTPN13 and KLF9 levels and Schwann cell proliferation

The Hippo pathway is a key regulatory pathway that is tightly regulated by mechanical cues such as tension, pressure, and contact with the extracellular matrix and other cells. At the distal end of the pathway is the yes-associated protein (YAP), a well-characterized transcriptional regulator. Through binding to transcription factors such as the TEA Domain TFs (TEADs) YAP regulates expression of several genes involved in cell fate, proliferation and death decisions. While the function of YAP as direct transcriptional regulator has been extensively characterized, only a small number of studies examined YAP function as a regulator of gene expression via microRNAs. We utilized bioinformatic approaches, including chromatin immunoprecipitation sequencing and RNA-Seq, to identify potential new targets of YAP regulation and identified miR-30a as a YAP target gene in Schwann cells. We find that YAP binds to the promoter and regulates the expression of miR-30a. Moreover, we identify several YAP-regulated genes that are putative miR-30a targets and focus on two of these, protein tyrosine pohosphatase non-receptor type 13 (PTPN13) and Kruppel like factor 9. We find that YAP regulation of Schwann cell proliferation and death is mediated, to a significant extent, through miR-30a regulation of PTPN13 in Schwann cells. These findings identify a new regulatory function by YAP, mediated by miR-30a, to downregulate expression of PTPN13 and Kruppel like factor 9. These studies expand our understanding of YAP function as a regulator of miRNAs and illustrate the complexity of YAP transcriptional functions.