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

ABSTRACT: 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 (TFs) 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 ChIP-seq 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, PTPN13 and KLF9. We find that YAP regulation of Schwann cell proliferation 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 KLF9. These studies expand our understanding of YAP function as a regulator of miRNAs and illustrate the complexity of YAP transcriptional functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163079 | GEO | 2021/07/09

REPOSITORIES: GEO

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Project description:The regulation of gene expression in cells, including by microRNAs (miRNAs), is a dynamic process. Current methods for identifying microRNA targets by combining sequence, miRNA and mRNA expression data do not adequately utilize the temporal information and thus miss important miRNAs and their targets. We developed a new method, mirDREM, that uses probabilistic modeling to reconstruct dynamic regulatory networks which explain how temporal gene expression is jointly regulated by microRNAs and transcription factors (TFs). We used mirDREM to study the regulation of postnatal lung development in mice. The reconstructed network for this process identified several known miRNAs and TFs and provided novel predictions about additional miRNAs and the specific developmental phases they regulate. Microarray data of Mouse Lung Epithelial cells MLE-12 after transfection with inhibitors for miR-30a, miR-30d, miR-23b and miR-125 and with precursors for miR-337, miR-466a, miR466d and miR-476c. The results provide a general insight into the gene expression profile which was modulated by the inhibition or overexpression of these microRNAs. We experimentally validated several predictions and show that miR-30d, miR-30a, and miR-467c are new regulators of proliferation in lung cells. Our analysis establishes new links between identified miRNAs and lung diseases, supporting recent evidence that such diseases may represent reversal of lung differentiation. We first analyzed the endogenous expression of miR-30a, miR-30d, miR-23b, miR-125, miR-337, miR-466a, miR466d and miR-476c in MLE-12 cells. Then, we transfected the MLE-12 cells with inhibitors ( miR-30a, miR-30d, miR-23b and miR-125) for the highly expressed and precursos for those that were almost undetectable (miR-337, miR-466a, miR466d and miR-476c). RNA level of the 8 microRNAs was verify by qRT-PCR in order to validate the transfection efficiency. Finally, 0.5ug of total RNA was used to performe the gene expression microarrays for each condition

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

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