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Long noncoding RNA ROCR contributes to SOX9 expression and chondrogenic differentiation of human mesenchymal stem cells

ABSTRACT: Long non-coding RNAs (lncRNAs) are expressed in a highly tissue-specific manner where they function in various aspects of cell biology, often as key regulators of gene expression. In this study we established a role for lncRNAs in chondrocyte differentiation. Using RNA sequencing we identified a human articular chondrocyte repertoire of lncRNAs from normal hip cartilage donated by neck of femur fracture patients. Of particular interest are lncRNAs upstream of the master chondrocyte transcription factor SOX9 locus. SOX9 is an HMG-box transcription factor which is essential for chondrocyte development by directing the expression of chondrocyte specific genes. Two of these lncRNAs are upregulated during chondrogenic differentiation of MSCs. Depletion of one of these lncRNA, LOC102723505, which we termed ROCR (regulator of chondrogenesis RNA), by RNAi disrupted MSC chondrogenesis, concomitant with reduced cartilage-specific gene expression and incomplete matrix component production, indicating an important role in chondrocyte biology. Specifically, SOX9 induction was significantly ablated in the absence of ROCR, and overexpression of SOX9 rescued the differentiation of MSCs into chondrocytes. Our work sheds further light on chondrocyte specific SOX9 expression and highlights a novel method of chondrocyte gene regulation involving a lncRNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107308 | GEO | 2017/11/28

SECONDARY ACCESSION(S): PRJNA419739

REPOSITORIES: GEO

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Project description:We compared Sox9-association at chondrocyte targets to a broad catalogue of regulatory indicators of chromatin organization and transcriptional activity to determine Sox9’s direct regulatory actions in normal developing chondrocytes. Sox9-associated regions resolve into two distinct regulatory categories. Class I regions closely associate with transcriptional start sites (TSSs). Their targets reflect general regulators of basal cell activities that Sox9 engages indirectly though a likely association with the basal transcriptional complex. In contrast, Class II regions outside of the local TSS domains highlight evolutionarily conserved, active enhancers directing expression of chondrocyte specific target genes, though DNA binding of Sox9-dimers at target sites with sub-optimal binding affinity. The level of associated chondrocyte gene expression correlates with the number of enhancer modules around the target gene and grouping into super-enhancer clusters. Comparison of Sox9 programs between neural crest and mesoderm-derived chondrocytes points to similar modes of chondrocyte specification in distinct chondrocyte lineages. These data provide the first insight into mammalian Sox family actions at the genome scale in the vivo setting. The resulting enhancer sets provide a key resource for further dissection of the regulatory programs of mammalian chondrogenesis. Incorportation of ChIP-seq data of Sox9 and histone modification marks for chromatin status together with microrarray gene expression profiling in neonatal mice chondrocytes to uncover Sox9 regulatory system

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Distinct regulatory programs for Sox9 in transcriptional regulation of the developing mammalian chondrocyte [RNA-seq]

Project description:We compared Sox9-association at chondrocyte targets to a broad catalogue of regulatory indicators of chromatin organization and transcriptional activity to determine Sox9’s direct regulatory actions in normal developing chondrocytes. Sox9-associated regions resolve into two distinct regulatory categories. Class I regions closely associate with transcriptional start sites (TSSs). Their targets reflect general regulators of basal cell activities that Sox9 engages indirectly through a likely association with the basal transcriptional complex. In contrast, Class II regions outside of the local TSS domains highlight evolutionarily conserved, active enhancers directing expression of chondrocyte specific target genes, though DNA binding of Sox9-dimers at target sites with sub-optimal binding affinity. The level of associated chondrocyte gene expression correlates with the number of enhancer modules around the target gene and grouping into super-enhancer clusters. Comparison of Sox9 programs between neural crest and mesoderm-derived chondrocytes points to similar modes of chondrocyte specification in distinct chondrocyte lineages. These data provide the first insight into mammalian Sox family actions at the genome scale in the vivo setting. The resulting enhancer sets provide a key resource for further dissection of the regulatory programs of mammalian chondrogenesis. Incorportation of ChIP-seq data of Sox9 and histone modification marks for chromatin status together with micorarray gene expression profiling in neonatal mice chondrocytes to uncover Sox9 regulatory system. Overexpression of Sox9 with a control of EGFP in human fibroblasts to identify the direct targets of Sox9 regulatory system

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Distinct regulatory programs for Sox9 in transcriptional regulation of the developing mammalian chondrocyte [ChIP-seq]

Project description:We compared Sox9-association at chondrocyte targets to a broad catalogue of regulatory indicators of chromatin organization and transcriptional activity to determine Sox9’s direct regulatory actions in normal developing chondrocytes. Sox9-associated regions resolve into two distinct regulatory categories. Class I regions closely associate with transcriptional start sites (TSSs). Their targets reflect general regulators of basal cell activities that Sox9 engages indirectly though a likely association with the basal transcriptional complex. In contrast, Class II regions outside of the local TSS domains highlight evolutionarily conserved, active enhancers directing expression of chondrocyte specific target genes, though DNA binding of Sox9-dimers at target sites with sub-optimal binding affinity. The level of associated chondrocyte gene expression correlates with the number of enhancer modules around the target gene and grouping into super-enhancer clusters. Comparison of Sox9 programs between neural crest and mesoderm-derived chondrocytes points to similar modes of chondrocyte specification in distinct chondrocyte lineages. These data provide the first insight into mammalian Sox family actions at the genome scale in the vivo setting. The resulting enhancer sets provide a key resource for further dissection of the regulatory programs of mammalian chondrogenesis. Incorportation of ChIP-seq data of Sox9 and histone modification marks for chromatin status together with micorarray gene expression profiling in neonatal mice chondrocytes to uncover Sox9 regulatory system. Overexpression of Sox9 with a control of EGFP in human fibroblasts to identify the direct targets of Sox9 regulatory system

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Mechanistic study comparing cartilage formation from human mesenchymal stromal cells and iPSC-derived multipotent cells [bulk RNA-seq]

Project description:Multipotent progenitor cells (iMPCs) created from induced pluripotent stem cells (iPSCs) is a promising cell source for cartilage regeneration. In most studies, bone morphogenetic proteins (BMPs) were shown to significantly enhance transforming growth factor-b (TGFb)-induced iMPC chondrogenesis. In contrast, TGFb alone is sufficient to induce robust chondrogenesis of human primary mesenchymal stromal cells (MSCs). Currently, the mechanism underlying this difference between iMPCs and MSCs has not been fully understood. In this study, we first generated iMPCs from human iPSCs and examined their differentiation capacity at different passages. We then optimized the conditions for chondrogenesis and determined that medium supplemented with TGFb and BMP6 led to robust cartilage formation from iMPCs with minimal hypertrophy. Moreover, the cartilage generated from this new method was resistant to osteogenic transition upon subcutaneous implantation and led to a hyaline cartilage-like regeneration in osteochondral defects in rats. Interestingly, TGFb alone induced phosphorylation of Smad2/3 in iMPCs but not Smad1/5, which led to poor chondrogenesis. In contrast, TGFb resulted in the phosphorylation of both Smad2/3 and Smad1/5 and robust chondrogenesis in human MSCs. We further discovered that the remarkably low level of Activin receptor-like kinase 1 (ACVRL1/ALK1) in iMPCs, when compared to MSCs, partially accounts for this difference. For instance, overexpression of ALK1 in iMPCs activated both Smad1/5 and Smad2/3 upon TGFb only treatment and resulted in a high level of chondrogenesis, which was not observed in control iMPCs. In summary, this study describes a robust method to generate chondrocytes with low hypertrophy for hyaline cartilage repair and elucidates the difference between MSCs and iMPCs in response to TGFb.

2022-12-20 | GSE197169 | GEO

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