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The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ChIP-seq]

ABSTRACT: Oligodendrocytes are the primary producers of many extracellular matrix (ECM) related proteins found in the central nervous system (CNS), thereby, these cells play a critical role in the determination of brain stiffness, node of Ranvier formation, perinodal ECM deposition and perineuronal net formation. The transcription factors that control ECM related gene expression in oligodendrocytes remain unknown. Here, we found that the transcription factor Osterix (also known as Sp7) binds in proximity to genes important for CNS ECM and node of Ranvier formation and mediates their expression. Oligodendrocyte specific ablation of Sp7 changes ECM composition and brain stiffness, and results in aberrant node of Ranvier formation. Sp7 is known to control osteoblast maturation and bone formation. Our comparative analyses suggests that Sp7 plays a conserved biological role in oligodendrocytes and in bone forming cells, where it mediates brain and bone tissue stiffness by controlling the expression of ECM components.

ORGANISM(S): Mus musculus

PROVIDER: GSE221191 | GEO | 2023/09/11

REPOSITORIES: GEO

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Project description:Treating recurrent GBM is a clinical challenge due to its highly resistant and aggressive nature. In order to develop new therapeutic targets for recurrent GBM a better understanding of its molecular landscape is necessary. Here we used a cellular model, developed in our lab which generates paired primary and recurrent samples from GBM cell lines and primary patient samples hence allowing us to compare the molecular differences between the two populations. Total RNA seq analysis of parent and recurrent population of two cell lines and one patient sample revealed a significant upregulation of Extracellular matrix interaction in recurrent population. Since matrix stiffness plays a pivotal role in cell-ECM interaction and downstream signaling, we developed a system that mimicked the brain like substrate stiffness by using collagen coated polyacrylamide-based substrate whose stiffness can be modified from normal brain (0.5kPa) to tumorigenic (10kPa). Using these substrates, we were able to capture the morphological and physiological differences between parent and recurrent GBM which were not evident on plastic surfaces (~1 GPa). On 0.5kPa, unlike circular parent cells, recurrent GBM cells showed two morphologies (circular and elongated). The recurrent cells growing on 0.5kPa also showed higher proliferation, invasion, migration and in-vivo tumorigenicity in orthotropic GBM mouse model, compared to parent cells. Furthermore, recurrent cells exhibited elevated velocity irrespective of substrate stiffness, which indicated that recurrent cells may possess inherent differential mechanosignalling ability which was reflected by higher expression of ECM proteins like Collagen IVA, MMP2 and MMP9. Moreover, mice brain injected with recurrent cells grown on 0.5kPa substrate showed higher Young’s modulus values suggesting that recurrent cells conditioned on 0.5kPa make the surrounding ECM stiffer. Importantly, inhibition of EGFR signaling, that is amplified with tissue stiffening in GBM resulted in decreased invasion, migration and proliferation in 0.5kPa recurrent cells, but interestingly survival remained unaffected, highlighting the importance of mimicking the physiological stiffness of the brain mimicking clinical scenario. Total RNA seq analysis of parent and recurrent cells grown on plastic and 0.5kPa substrate identified PLEKHA7 as significantly upregulated gene specifically in 0.5kPa recurrent sample. Higher protein expression of PLEKHA7 in recurrent GBM as compared to primary GBM was validated in patient biopsies. Accordingly, PLEKHA7 knockdown reduced invasion and survival of recurrent GBM cells. Together, these data provides a model system that captures the differential mechanosensing signals of primary and recurrent GBM cells and identifies a novel potential target specific for recurrent GBM.

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The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ChIP-seq]

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