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Runx1 and Runx3 cooperatively repress Pmp22 to drive neurofibromagenesis [ChIP-seq]

ABSTRACT: Neurofibromatosis type 1 (NF1) patients are predisposed to develop neurofibromas but the underlying molecular mechanism(s) of neurofibromagenesis are not fully understood. We showed that dual genetic deletion of Runx1 (Rx1) and Runx3 (Rx3) in Schwann cells (SCs) and Schwann cell precursors (SCPs) significantly delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to tumor initiation. Knockdown of Pmp22 with shRNAs increased Rx1fl/fl;Rx3fl/fl;Nf1fl/fl;DhhCre sphere numbers and enabled significantly more neurofibroma like micro-lesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased proliferation. Mechanistically, Rx1/3 regulated alterative Pmp22 promoter usage and reduced post transcriptional expression of Pmp22. Finally, pharmacological inhibition of Runx/core binding factor beta (Cbf-β) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a novel signaling pathway involving Rx1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of Runx/Cbf-β interaction might provide a novel therapy for neurofibroma patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE122775 | GEO | 2019/05/01

REPOSITORIES: GEO

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Runx1 and Runx3 cooperatively repress Pmp22 to drive neurofibromagenesis [microarray]

Project description:Neurofibromatosis type 1 (NF1) patients are predisposed to develop neurofibromas but the underlying molecular mechanism(s) of neurofibromagenesis are not fully understood. We showed that dual genetic deletion of Runx1 (Rx1) and Runx3 (Rx3) in Schwann cells (SCs) and Schwann cell precursors (SCPs) significantly delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to tumor initiation. Knockdown of Pmp22 with shRNAs increased Rx1fl/fl;Rx3fl/fl;Nf1fl/fl;DhhCre sphere numbers and enabled significantly more neurofibroma like micro-lesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased proliferation. Mechanistically, Rx1/3 regulated alterative Pmp22 promoter usage and reduced post transcriptional expression of Pmp22. Finally, pharmacological inhibition of Runx/core binding factor beta (Cbf-β) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a novel signaling pathway involving Rx1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of Runx/Cbf-β interaction might provide a novel therapy for neurofibroma patients.

2019-05-01 | GSE122773 | GEO

Runx1 and Runx3 cooperatively repress Pmp22 to drive neurofibromagenesis [ATAC-seq]

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Runx1 and Runx3 cooperatively repress Pmp22 to drive neurofibromagenesis [RNA-seq]

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Modeling the pathogenesis of Charcot-Marie-Tooth disease type 1A using patient-specific iPSCs

Project description:Here, human induced pluripotent stem cells (control-hiPSCs, CMT1A-hiPSCs, and PMP22-hiPSCs) were induced to differentiate to Schwann cells (control-SCs, CMT1A-SCs, and PMP22-SCs) through neural crest stage (control-NCSCs, CMT1A-NCSCs, and PMP22-NCSCs). We sequenced mRNA samples from Schwann cell differentiation of human pluripotent stem cells at 3 different stage to generate the gene expression profiles of these cells.

2018-02-14 | GSE97851 | GEO

Expression data of three sets of cells: (1) Schwann cells and macrophages from 1m-old WT DRG, (2) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 1m-old neurofibroma, (3) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 7m-old neurofibroma

2017-05-01 | GSE78901 | GEO

Project description:Schwann cells and macrophages were dissociated from normal DRGs and 1- and 7-month-old neurofibroma. Schwann cells from neurofibroma have Nf1-/- phenotypes. All macrophages have Nf1+/+ phenotypes. We used microarrays (Affymetrix MoGene 2.0 ST GeneChip) to detect transcriptomal changes between 7-month-old neurofibroma Schwann cells (or macrophages) versus 1-month-old wild-type (or neurofibroma) Schwann cells (or macrophages). Expression data of three sets of cells: (1)Schwann cells and macrophages from 1-month-old wild-type mouse dorsal root ganglia, (2) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 1-month-old neurofibroma, (3) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 7-month-old neurofibroma We chopped mouse DRG/neurofibromas into 1-3 mm^3 pieces and plated them in dissociation medium containing 20mL L-15 (Mediatech), 0.5 mg/mL collagenase type 1 (Worthington; Lakewood, NJ), and 2.5 mg/mL dispase protease type II (Cambrex; East Rutherford, NJ) at 37Â°C for 4-6 hours with shaking. The dissociation reaction was stopped by adding DMEM +10%FBS. Undigested DRG/tumors were excluded by 100ÂµM cell strainer. Cells were collected by centrifugation. For each microarrays (Schwann cell, macrophage), Affymetrix GeneChip Command Console (v4.0.0) was used to create .chp files. All the probe sets on Affymetrix Mouse Gene 2.0 ST array (Mogene-2_0-st-v1.na33.2.mm10) were summarized by Affymetix Expression Console program using robust multi-chip average (RMA) method . After preprocessing steps, data from two batches were combined and their batch effects were corrected using ComBat method Please note that [1] all MP samples are Nf1+/+ (no mutation on Nf1 gene) and the only difference is their ages (1month, 7month) and [2] the 'nf1' in sample title reperesents "neurofibroma type1 disease", not "Nf1 gene".

2017-05-01 | E-GEOD-78901 | biostudies-arrayexpress

Expression profiling of Runx2 and CBFbeta siRNA treatment

Project description:Cells of MDA-MB-231 breast cancer cell-line were transfected with siRNA against Runx2, CBF-beta or non-specific siRNA used as control. Runx2 is a member of the Runx transcription factor family and possesses a Runt domain capable of binding to the consensus DNA sequence ACC(A/G)CA. This domain also interacts with the co-activator protein core binding factor beta (CBF-beta), which enhances its binding to DNA. Runx2, primarily identified as a master regulator of bone development, but was also found expressed in the epithelium of the nascent mammary gland in mice. In contrast with its normal role in breast, it has been shown that Runx2 is over-expressed in breast cancer cell lines.

2011-10-19 | E-MEXP-3230 | biostudies-arrayexpress

Integrative genomic analyses of neurofibromatosis tumors identify SOX9 as biomarker and survival gene

Project description:Understanding biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumors is essential, as tumor biomarkers, prognostic factors and therapeutics are all lacking. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n = 10), NF1-derived primary benign neurofibroma Schwann cells (n = 22), malignant peripheral nerve sheath tumor (MPNST) cell lines (n = 13), benign neurofibromas (n = 26) and MPNST (n = 6). Dermal and plexiform neurofibromas were indistinguishable. A prominent theme in the analysis was aberrant differentiation. Neurofibromas repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes upregulated in the sarcomas were significantly enriched for genes activated in neural crest cells. We validated differential expression of 82 genes including the neural crest transcription factor SOX9 and SOX9 predicted targets. SOX9 immunoreactivity was robust in neurofibroma and MPSNT tissue sections and targeting SOX9 - strongly expressed in NF1-related tumors - caused MPNST cell death. SOX9 is a biomarker of neurofibroma and MPNST, and possibly a therapeutic target in NF1. Keywords: tumor stage 86 microarrays, consisting of 77 samples and 9 batch reference samples: NHSC (10), dNFSC (11), pNFSC (11), MPNST cell lines (13), dNF (13), pNF (13), MPNST (6)

2009-07-15 | E-GEOD-14038 | biostudies-arrayexpress

Kinome and Rho-GTPase Synthetic Lethal shRNA Library Screen in paired NF1-/- and GAP-Related Domain Restored Schwann Cells

Project description:To identify possible novel targets for the treatment of plexiform neurofibroma formation through a synthetic lethal shRNA library screen in the tumorigenic cell of origin, Schwann cells.

2019-11-30 | E-MTAB-8398 | biostudies-arrayexpress

Scalable generation of Schwann cell precursors from human pluripotent stem cells

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2017-08-15 | GSE95004 | GEO

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