Transcriptional regulation of miR-30a by YAP impacts PTPN13 and KLF9 levels and Schwann cell proliferation
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PROVIDER: PRJNA684617 | ENA |
REPOSITORIES: ENA
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Project description: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.
2021-07-09 | GSE163079 | GEO
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Project description:Myelination is essential for nervous system function. Schwann cells interact with neurons and with the basal lamina to sort and myelinate axons, using known receptors and signaling pathways. In contrast, the transcriptional control of axonal sorting and the role of mechano-transduction in myelination are largely unknown. Yap and Taz are effectors of the Hippo pathway that integrate chemical and mechanical signals in cells. Here, we describe a previously unknown role for the Hippo pathway in myelination. Using conditional mutagenesis in mice we show that Taz is required in Schwann cells for radial sorting and myelination. Yap is redundant with Taz as ablation of both Yap and Taz abolishes radial sorting. Yap/Taz regulate Schwann cell proliferation and transcription of basal lamina receptors, both necessary for proper radial sorting of axons, and subsequent myelination. These data link transcriptional effectors of the Hippo pathway and of mechanotransduction to myelin formation in Schwann cells.
2016-06-06 | GSE79115 | GEO
Project description:RNA-sequencing was performed to gain insight into the transcriptome-wide molecular changes induced by miR-30a-5p or miR-30a-3p over-expression in lung adenocarcinoma cells. Following transfection of miR-30a-5p or miR-30a-3p miRNA mimic or control RNA, RNA-sequencing was performed. This high-throughput data revealed elevated expression of both miR-30a-5p and miR-30a-3p reduced the expression of genes and pathways known to induce proliferation and movement in lung adenocarcinoma cells.
2020-02-26 | GSE142695 | GEO
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage derived sarcomas with poor prognosis. The molecular events underlying SC lineage cells-to-MPNST transformation remain elusive. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyper-proliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide target profiling reveals that TAZ/YAP-TEAD1 directly activates a set of oncogenic programs in SCs including PDGFR/RAF signaling. Co-targeting TAZ/YAP and PDGFR/RAF signaling efficaciously reduces tumorigenicity in Lats1/2-deficient tumors. Thus, our findings establish a previously unrecognized convergence between LATS1/2-TAZ/YAP pathway and MPNST pathogenesis, suggesting that combined inhibition of TAZ/YAP-PDGFR/RAF signaling may be beneficial in MPNSTs.
2018-02-13 | GSE99040 | GEO
Project description:To identify putative target genes of the transcription factor Klf9 in primary keratinocytes we over-expressed Klf9 in these cells using a lentiviral delivery system. We detected several hundred genes that show differential expression levels following ectopic Klf9 expression including several genes that are involved in proliferation and cell cycle control. These results allow insights into the mechanisms by which Klf9 regulates proliferation in primary keratinocytes. Primary human neonatal foreskin keratinocytes were infected with equal viral titers of a GFP and KLF9 expression construct, respectively. Cells were harvested 2,4 and 7 days after infection and total RNA was used to perform whole genome microarray analysis.
2012-07-30 | E-GEOD-36014 | biostudies-arrayexpress
Project description:Kruppel-like factor 9 (Klf9), a zinc-finger transcription factor, is implicated in the control of cell proliferation, cell differentiation and cell fate in brain and uterus. Using Klf9 null mutant mice, we have investigated the involvement of Klf9 in small intestine crypt-villus cell renewal and lineage determination. We report the predominant expression of Klf9 gene in small intestine smooth muscle (muscularis externa). Jejunums null for Klf9 have shorter villi, reduced crypt stem/transit cell proliferation, and altered lineage determination as indicated by decreased and increased numbers of Goblet and Paneth cells, respectively. A stimulatory role for Klf9 in villus cell migration was demonstrated by BrdU labeling. Results suggest that Klf9 controls the elaboration, from small intestine smooth muscle, of molecular mediator(s) of crypt cell proliferation and lineage determination, and of villus cell migration. Experiment Overall Design: Total RNA was extracted in parallel from the jejunums of five WT and five Klf9-/- male mice (PND 30) using TRIzol reagent (Invitrogen, Carlsbad, CA). Conversion of each RNA preparation to corresponding fragmented cRNA. Fifteen ug of each cRNA was hybridized for 16 hours to an Affymetrix mouse 430A GeneChip. Ten GeneChips (each corresponding to a single animal) were hybridized, washed and scanned in parallel. Following the wash, signal amplification, and signal detection steps, GeneChips were scanned (Agilent GeneArray laser scanner) and the resultant images quantified using Affymetrix MAS 5.0 software.
2007-11-15 | E-GEOD-6443 | biostudies-arrayexpress
Project description:Schwann cell (SC) myelination in the peripheral nervous system is essential for motor function, and uncontrolled SC proliferation occurs in cancer. Here, we show that a dual direct role for Hippo effectors TAZ and YAP in regulation of SC proliferation and myelination through modulating G protein expression and interacting with SOX10, respectively. Developmentally-regulated mutagenesis indicates that TAZ/YAP are critical for SC proliferation yet also required for their differentiation and myelination. Genome-wide occupancy mapping and transcriptome profiling reveal that nuclear TAZ and YAP promote SC proliferation by activating cell cycle regulators, while targeting critical differentiation regulators in cooperation with SOX10 for myelination. We further identified that TAZ targets and represses Gnas, encoding Gαs-protein, which opposes TAZ/YAP activities to decelerate proliferation. Gnas deletion expands SC precursor pools and blocks myelination in the sciatic nerve. Thus, our study revealed that the Hippo/TAZ/YAP and Gαs-protein feedback circuit functions as a fulcrum balancing SC proliferation and differentiation, providing insights into molecular programming of SC lineage progression and homeostasis.
2017-04-26 | GSE94990 | GEO
Project description:Human miR-30a-3p was knocked-down in HepG2 using siRNA duplex against the miRNA precursor, and compared to control cells on GeneChip to identify the target transcripts against miR-30a-3p in vivo.
2006-01-01 | E-MEXP-456 | biostudies-arrayexpress
Project description:To identify putative target genes of the transcription factor Klf9 in primary keratinocytes we over-expressed Klf9 in these cells using a lentiviral delivery system. We detected several hundred genes that show differential expression levels following ectopic Klf9 expression including several genes that are involved in proliferation and cell cycle control. These results allow insights into the mechanisms by which Klf9 regulates proliferation in primary keratinocytes.
2012-07-31 | GSE36014 | GEO