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SOX9 is dispensable to initiate epigenetic remodeling and activation of marker genes at the onset of chondrogenesis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE114522 | GEO | 2018/07/02

REPOSITORIES: GEO

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SOX9 is dispensable for the initiation of epigenetic remodeling and the activation of marker genes at the onset of chondrogenesis.

Project description:SOX9 controls cell lineage fate and differentiation in major biological processes. It is known as a potent transcriptional activator of differentiation-specific genes, but its earliest targets and its contribution to priming chromatin for gene activation remain unknown. Here, we address this knowledge gap using chondrogenesis as a model system. By profiling the whole transcriptome and the whole epigenome of wild-type and Sox9-deficient mouse embryo limb buds, we uncover multiple structural and regulatory genes, including Fam101a, Myh14, Sema3c and Sema3d, as specific markers of precartilaginous condensation, and we provide evidence of their direct transactivation by SOX9. Intriguingly, we find that SOX9 helps remove epigenetic signatures of transcriptional repression and establish active-promoter and active-enhancer marks at precartilage- and cartilage-specific loci, but is not absolutely required to initiate these changes and activate transcription. Altogether, these findings widen our current knowledge of SOX9 targets in early chondrogenesis and call for new studies to identify the pioneer and transactivating factors that act upstream of or along with SOX9 to prompt chromatin remodeling and specific gene activation at the onset of chondrogenesis and other processes.

| S-EPMC6078338 | biostudies-literature

SOX9 is dispensable to initiate epigenetic remodeling and activation of marker genes at the onset of chondrogenesis (ChIP-Seq)

Project description:Using whole-transcriptome and whole-epigenome sequencing approaches for wild-type and Sox9-deficient mouse embryo limb buds, we here identify genes specifically expressed and likely involved in precartilaginous condensation. We show that SOX9 directly upregulates these genes and well-known early-cartilage markers, and that its actions in chondrogenic cells have little impact on neighboring cell types. Intriguingly, we find that SOX9 helps remove epigenetic signatures of transcriptional repression and establish active-promoter and active-enhancer marks at precartilage- and cartilage-specific loci, but is not absolutely required to initiate these changes and activate transcription. Altogether, these findings widen our current knowledge of SOX9 targets in early chondrogenesis and call for new studies to identify the pioneer and transactivating factors that act upstream of or along with SOX9 to prompt chromatin remodeling and specific gene activation at the onset of chondrogenesis and other processes.

2018-07-02 | GSE114520 | GEO

SOX9 is dispensable to initiate epigenetic remodeling and activation of marker genes at the onset of chondrogenesis (RNA-Seq)

2018-07-02 | GSE114521 | GEO

SOX9 is dispensable to initiate epigenetic remodeling and activation of marker genes at the onset of chondrogenesis

Project description:SOX9 is dispensable to initiate epigenetic remodeling and activation of marker genes at the onset of chondrogenesis

| PRJNA471673 | ENA

SOX9 is dispensable to initiate epigenetic remodeling and activation of marker genes at the onset of chondrogenesis (RNA-Seq)

Project description:SOX9 is dispensable to initiate epigenetic remodeling and activation of marker genes at the onset of chondrogenesis (RNA-Seq)

| PRJNA471676 | ENA

SOX9 is dispensable to initiate epigenetic remodeling and activation of marker genes at the onset of chondrogenesis (ChIP-Seq)

Project description:SOX9 is dispensable to initiate epigenetic remodeling and activation of marker genes at the onset of chondrogenesis (ChIP-Seq)

| PRJNA471677 | ENA

Transcriptional coactivator PGC-1alpha regulates chondrogenesis via association with Sox9.

Project description:Chondrogenesis is a multistep pathway in which multipotential mesenchymal stem cells (MSC) differentiate into chondrocytes. The transcription factor Sox9 (SRY-related high mobility group-Box gene 9) regulates chondrocyte differentiation and cartilage-specific expression of genes, such as Col2a1 (collagen type II alpha1). However, Sox9 expression is detected not only in chondrogenic tissue but also in nonchondrogenic tissues, suggesting the existence of a molecular partner(s) required for Sox9 to control chondrogenesis and chondrogenic gene expression. Here, we report identification of peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) as a coactivator for Sox9 during chondrogenesis. Expression of PGC-1alpha is induced at chondrogenesis sites during mouse embryonic limb development and during chondrogenesis in human MSC cultures. PGC-1alpha directly interacts with Sox9 and promotes Sox9-dependent transcriptional activity, suggesting that PGC-1alpha acts as a transcriptional coactivator for Sox9. Consistent with this finding, PGC-1alpha disruption in MSC by small interfering RNA inhibits Col2a1 expression during chondrogenesis. Furthermore, overexpression of both PGC-1alpha and Sox9 induced expression of chondrogenic genes, including Col2a1, followed by chondrogenesis in the MSC and developing chick limb. Together, our results suggest a transcriptional mechanism for chondrogenesis that is coordinated by PGC-1alpha.

| S-EPMC548985 | biostudies-literature

Kindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis.

Project description:The signals that control skeletogenesis are incompletely understood. Here we show that deleting Kindlin-2 in Prx1-expressing mesenchymal progenitors in mice causes neonatal lethality, chondrodysplasia and loss of the skull vault. Kindlin-2 ablation reduces chondrocyte density by decreasing cell proliferation and increasing apoptosis, and disrupts column formation, thus impairing the formation of the primary ossification center and causing severe limb shortening. Remarkably, Kindlin-2 localizes to not only focal adhesions, but also to the nuclei of chondrocytes. Loss of Kindlin-2 reduces, while the overexpression of Kindlin-2 increases, Sox9 expression. Furthermore, the overexpression of Sox9 restores the defects in chondrogenic differentiation induced by Kindlin-2 deletion in vitro. In addition, Kindlin-2 ablation inhibits TGF-β1-induced Smad2 phosphorylation and chondrocyte differentiation. Finally, deleting Kindlin-2 in chondrocytes directly impairs chondrocyte functions, resulting in progressive dwarfism and kyphosis in mice. These studies uncover a previously unrecognized function for Kindlin-2 and a mechanism for regulation of the chondrocyte differentiation programme and chondrogenesis.

| S-EPMC4498276 | biostudies-literature

Profiling of Sox9-related genes in chondrogenesis using Sox9-3'EGFP knock-in and Sox9-EGFP/EGFP null chimeric mouse embryos

Project description:To define the repertoire of Sox9-dependent genes that contribute to the regulation of chondrogenesis, we generated Sox9-3'enhanced green fluorescent protein (EGFP) knock-in mice (Sox9-3'EGFP) and Sox9-EGFP/EGFP null chimeras. EGFP-positive cells of Sox9-3'EGFP knock-in and Sox9-EGFP/EGFP null chimeric embryos harvested from limb buds at embryonic day 12.5 were sorted using a FACSAria flow cytometer (Becton-Dickinson). Total RNA of sorted cells was extracted using the RNeasy Mini Kit (QIAGEN) and amplified according to the instructions provided by Affymetrix. Microarray analysis using the Affymetrix Mouse Genome 430 2.0 Array was performed according to the manufacturer's instructions.

2011-02-16 | E-MTAB-537 | biostudies-arrayexpress

ADAM10 modulates SOX9 expression <i>via</i> N1ICD during chondrogenesis at the cranial base.

Project description:The cranial base is the foundation of the craniofacial structure, and any interruption of the cranial base can lead to facial deformity. The cranial base develops from two synchondroses via endochondral ossification. Chondrogenesis is an important step in endochondral ossification. A disintegrin and metalloprotease (ADAM) 10 participates in the Notch1 signalling pathway, which has been reported to regulate chondrogenesis via a SOX9-dependent mechanism. However, little is known about the function of ADAM10 in chondrogenesis. In this study, adam10-conditional-knockout (cKO) mice exhibited sharper naso-labial angles and flatter skulls than wild-type (WT) mice. In the sagittal plane, SOX9 was more widespread in the cranial base in Adam10-cKO mice than in WT mice. For in vitro experiments, we used the ATDC5 cell line as a model to investigate the role of ADAM10 in chondrogenesis. Plasmid 129 was designed to decrease the expression of Adam10; the resulting downregulation of Adam10 reduced the production of N1ICD. Plasmid 129 increased the expression of SOX9 under chondrogenic induction, and this increase could be inhibited by transfection with exogenous N1ICD. Collectively, these results show that ADAM10 participates in chondrogenesis by negatively regulating SOX9 expression in an N1ICD-dependent manner during cranial base development.

| S-EPMC9089825 | biostudies-literature

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