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RUNX2 promotes pulmonary fibrosis through the conversion of alveolar fibroblasts into pathological fibroblasts

ABSTRACT: RUNX2 promotes pulmonary fibrosis through the conversion of alveolar fibroblasts into pathological fibroblasts

PROVIDER: PRJNA1167229 | ENA |

REPOSITORIES: ENA

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RUNX2 promotes pulmonary fibrosis through the conversion of alveolar fibroblasts into pathological fibroblasts

Project description:A hallmark of pulmonary fibrosis is aberrant activation of lung fibroblasts into pathological fibroblasts producing excessive extracellular matrix (ECM). Thus, identification of key regulator(s) driving the generation of pathological fibroblasts can inform effective countermeasures against disease progression. In this study, we show that Leptin Receptor (Lepr)+ fibroblasts arising during alveologenesis include Signal Peptide-CUB-EGF Domain-containing Protein 2 (Scube2)+ alveolar fibroblasts as a major constituent significantly contributing to collagen triple helix repeat containing 1 (Cthrc1)+ Periostin (Postn)+ pathological fibroblasts in two mouse models of pulmonary fibrosis. Genetic ablation of the Postn+ pathological fibroblasts attenuates fibrosis. Comprehensive analysis of single cell RNA sequencing (scRNA-seq) and single cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq) reveal Runt related transcription factor 2 (RUNX2) as a key regulator of fibrotic genes. Consistently, conditional deletion of Runx2 with Lepr-CreERT2 or Scube2-CreERT2 reduces the generation of pathological fibroblasts, ECM deposition, and pulmonary fibrosis. Therefore, Lepr+ derived fibroblasts which include Scube2+ alveolar fibroblasts are a key source of pathological fibroblasts, and targeting Runx2 provides a potential treatment option for pulmonary fibrosis.

2024-11-25 | GSE278419 | GEO

Conversion of human fibroblasts into vascular cells

Project description:This SuperSeries is composed of the following subset Series: GSE40793: Conversion of human fibroblasts into vascular cells (gene expression) GSE40909: Conversion of human fibroblasts into vascular cells (methylation) Refer to individual Series

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Peptidylarginine deiminase 2 (PADI2) is a key regulator for osteoblast differentiation and bone formation through the maintenance of citrullination-mediated RUNX2 stability

Project description:Peptidylarginine deiminase (PADI) 2 catalyzes the posttranslational conversion of peptidyl-arginine to peptidyl-citrulline, a process called citrullination. However, the exact function of PADI2 in bone development and bone homeostasis remains unknown. In this study, we found that Padi2 deficiency lead to loss of bone mass and cleidocranial dysplasia (CCD)-like phenotype with delayed calvarial ossification and clavicular hypoplasia due to impaired osteoblast differentiation. Mechanistically, Padi2 depletion drastically reduced RUNX2 protein level and PADI2 stabilized RUNX2 from ubiquitin-proteasomal degradation. Furthermore, we identified a new modification at RUNX2, citrullination of arginine and its conversion to citrulline by PADI2. PADI2 citrullinates RUNX2 via a direct physical interaction and the citrullination sites at RUNX2 by PADI2 were identified by high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Interestingly, in mouse RUNX2 isoform 1 (528 a.a), loss of R381, a citrullination site by PADI2, drastically reduced RUNX2 protein levels, indicating that the citrullination of RUNX2 by PADI2 is required for the maintenance of RUNX2 protein stability. Collectively, our study demonstrates that PADI2-mediated citrullination play key roles in bone formation and bone homeostasis. Also, CCD may result from functional defects of RUNX2 by Padi2 deficiency. These insights into the role of PADI2 in postnatal bone formation and homeostasis and CCD pathogenesis may assist in the development of new therapies for bone diseases including CCD.

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Transcriptome analysis of periodontitis-associated fibroblasts by CAGE sequencing identified DLX5 and RUNX2 long variant as novel regulators involved in periodontitis.

Project description:Transcriptome analyses of normal gingival fibroblasts after knockdown of DLX5 and RUNX2 long forms.

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Transcriptome analysis of periodontitis-associated fibroblasts by CAGE sequencing identified DLX5 and RUNX2 long variant as novel regulators involved in periodontitis

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Small molecules enable highly efficient neuronal conversion of human fibroblasts

Project description:Forced expression of pro-neural transcription factors was shown to mediate direct neuronal conversion of human fibroblasts. Since neurons are postmitotic, the conversion efficiency represents an important parameter. Here we present a minimalist approach combining two factor neuronal programming with small molecule-based inhibition of GSK3ß and SMAD signaling, which gives rise to functional neuron-like cells (iNs) of various neurotransmitter phenotypes with an overall yield of up to >200% and a final neuronal purity of up to >80%. Timcourse of reprogramming of fibroblasts towards an neuronal phenotype in two independent fibroblast lines

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Direct conversion of fibroblasts to neurons by a new mechanism – p53 regulation

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