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Erf chromatin binding-sites in E13.5 mouse embryo fibroblasts

ABSTRACT: We show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 , causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf reduced to ~30% of normal exhibit postnatal multisuture synostosis; by contrast, embryonic calvarial development appears mildly delayed. Using chromatin immunoprecipitation in mouse embryonic fibroblasts and high-throughput sequencing, we find that ERF binds preferentially to distal regulatory elements containing RUNX or AP1 motifs. This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes.

ORGANISM(S): Mus musculus

PROVIDER: GSE42936 | GEO | 2013/01/15

SECONDARY ACCESSION(S): PRJNA183890

REPOSITORIES: GEO

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Erf chromatin binding-sites in E13.5 mouse embryo fibroblasts

Project description:We show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 , causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf reduced to ~30% of normal exhibit postnatal multisuture synostosis; by contrast, embryonic calvarial development appears mildly delayed. Using chromatin immunoprecipitation in mouse embryonic fibroblasts and high-throughput sequencing, we find that ERF binds preferentially to distal regulatory elements containing RUNX or AP1 motifs. This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes. Examination of Erf binding site in E13.5 mouse embryo fibroblasts, growing in the presence or absence of serum for 4 hours

2013-01-15 | E-GEOD-42936 | biostudies-arrayexpress

Skeletal Stem Cell Powering Cranial Suture Fate: An Answer to Craniosynostosis (scRNA-seq)

Project description:Purpose: The cranial suture is a fibrous joint, and similar to the growth plates of the skeletal long bone, they serve as the major centers of calvarial vault morphogenesis. Our group’s identification of a skeletal stem cell isolated from the mouse tibial growth plate prompted us to investigate whether these skeletal stem cells are also resident in the mouse cranial sutures and if they govern postnatal suture patency or fusion. Results: We preformed a spatio-temporal profiling of the mouse cranial sutures by flow cytometry, demonstrating a significant decrease in the temporal representation of skeletal stem cells in fusing versus patent sutures. Moreover, canonical Wnt signaling has a significant impact on skeletal stem cells proliferation and thus representation within the suture, dictating fate: fusion or patency. Breeding an Axin2+/-LacZ mouse, with enhanced activation of canonical Wnt signaling to a Twist1+/− mouse, harboring a coronal craniosynostosis enriched the skeletal stem cell pool in coronal sutures, thereby preventing Twist1+/− craniosynostosis. Conclusions: Our findings suggest an imbalance and/or decrease in resident skeletal stem cells within the cranial sutures gives rise to craniosynostosis, however, restoring this representation by enriching skeletal stem cells within the suture can maintain patency.

2020-04-15 | GSE138881 | GEO

Skeletal Stem Cell Powering Cranial Suture Fate: An Answer to Craniosynostosis (bulk_RNA-seq)

2020-04-15 | GSE138880 | GEO

Gene Expression Changes Between Patent and Fused Cranial Sutures in a Nonsyndromic Craniosynostosis Population

Project description:Assaying gene expression in sutural bone fragments from patients diagnosed with non-syndromic craniosynostosis. Sutural fragments were collected from both the fused and patent cranial suture of infants during cranial vault reconstruction. Gene expression was compared between the patent and fused sutures using the paired t-test. The aim was to identify thoses genes significantly differentially expressed in fused suture relative to patent. Total RNA isolated from patent and fused human cranial sutures was assayed. Expression in synostosed suture was compared to patent suture.

2013-09-12 | E-GEOD-50796 | biostudies-arrayexpress

The developing mouse coronal suture at single-cell resolution

Project description:Sutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. In order to uncover the cellular diversity within sutures, we conducted single-cell transcriptomic and histological analyses of the embryonic murine coronal suture. We identify Erg and Pthlh as early markers of osteogenic progenitors in sutures, and distinct pre-osteoblast signatures between the bone fronts and periosteum. diverse mesenchymal layers at the coronal suture, including multiple distinct meningeal layers below the suture, and ligamentous, ectocranial, and hypodermal layers above the sutureIn the ectocranial layers above the suture, we observe a ligament-like population spanning the frontal and parietal bones and expressing genes implicated in mechanosensation. Mesenchyme in and around the coronal suture is asymmetrically distributed between the frontal and parietal bones, and we identify different states of osteogenic cells extending from the bone fronts into the more mature bone, and a potential signature for sutural stem cellsIn the meningeal layers, we detect a potential chondrogenic periosteal dura population that may be involved in endochondral ossification that closes sutures. Expression of genes mutated in craniosynostosis is spread across diverse cell types, suggesting multiple points at which homeostasis can fail. This single-cell atlas provides a resource to understand the development of the coronal suture, the suture most commonly fused in craniosynostosis.

2021-06-17 | GSE163693 | GEO

Gene Expression Changes Between Patent and Fused Cranial Sutures in a Nonsyndromic Craniosynostosis Population

2013-09-12 | GSE50796 | GEO

Single-cell analysis identifies a key role for Hhip in murine coronal suture development

Project description:Craniofacial development depends on formation and maintenance of sutures between bones of the skull. In sutures, growth occurs at osteogenic fronts along the edge of each bone and suture mesenchyme separates adjacent bones. We performed single-cell RNA-seq analysis of the embryonic, murine coronal suture. Seven populations at E16.5 and nine at E18.5 comprised the suture mesenchyme, osteogenic cells, and associated populations. Expression of Hhip, an inhibitor of hedgehog (HH) signaling, marked a mesenchymal population distinct from other neurocranial sutures. At E18.5, Hhip-/- coronal osteogenic fronts were closely apposed and HH signaling was increased throughout the depleted suture mesenchyme compared to WT, demonstrating that Hhip is required for normal coronal suture development. Tracing of the neonatal Hhip-expressing population showed that descendant cells persisted in the coronal suture and contributed to calvarial bone growth. Our transcriptomic approach provides a rich resource for insight into normal and abnormal development.

2021-06-26 | GSE178899 | GEO

Calvarial osteoblast transcriptome analysis identifies genetic targets and extracellular matrix-mediated focal adhesion as potential biomarkers for single-suture craniosynostosis

Project description:Craniosynostosis is a disease defined by premature fusion of one or more cranial sutures. The mechanistic pathology of isolated single-suture craniosynostosis is complex and while a number of genetic biomarkers and environmental predispositions have been identified, in many cases the causes remain controversial and inconclusive at best. After controlling for variables contributing to potential bias, FGF7, SFRP4, and VCAM1 emerged as potential genetic biomarkers for single-suture craniosynostosis due to their significantly large changes in gene expression compared to the control population. Furthermore, pathway analysis implicated focal adhesion and extracellular matrix (ECM)-receptor interaction as differentially regulated gene networks when comparing all cases of single-suture synostosis and controls. Lastly, overall gene expression was found to be highly conserved between coronal and metopic cases, as evidenced by the fact that WNT2 and IGFBP2 were the only differentially regulated genes identified in a direct comparison. These results not only confirm the roles of previously reported craniosynostosis-related targets but also introduce novel genetic biomarkers and pathways that may play critical roles in its pathogenesis.

2012-03-04 | GSE27976 | GEO

Expansion of the sagittal suture induces proliferation of skeletal stem cells and sustains endogenous calvarial bone regeneration

Project description:In newborn humans, and up to approximately 2 y of age, calvarial bone defects can naturally regenerate. This remarkable regeneration potential is also found in newborn mice and is absent in adult mice. Since previous studies showed that the mouse calvarial sutures are reservoirs of calvarial skeletal stem cells (cSSCs), which are the cells responsible for calvarial bone regeneration, here we hypothesized that the regenerative potential of the newborn mouse calvaria is due to a significant amount of cSSCs present in the newborn expanding sutures. Thus, we tested whether such regenerative potential can be reverse engineered in adult mice by artificially inducing an increase of the cSSCs resident within the adult calvarial sutures.First, we analyzed the cellular composition of the calvarial sutures in newborn and in older mice, up to 14-mo-old mice, showing that the sutures of the younger mice are enriched in cSSCs. Then, we demonstrated that a controlled mechanical expansion of the functionally closed sagittal sutures of adult mice induces a significant increase of the cSSCs. Finally, we showed that if a calvarial critical size bone defect is created simultaneously to the mechanical expansion of the sagittal suture, it fully regenerates without the need for additional therapeutic aids. Using a genetic blockade system, we further demonstrate that this endogenous regeneration is mediated by the canonical Wnt signaling.This study shows that controlled mechanical forces can harness the cSSCs and induce calvarial bone regeneration. Similar harnessing strategies may be used to develop novel and more effective bone regeneration autotherapies.

2023-04-11 | GSE227468 | GEO

Comparative tissue gene expression profiling and alternative splicing by exon-sensitive microarrays in non-syndromic craniosynostosis

Project description:Craniosynostosis (CS) is the congenital premature fusion of one or more cranial sutures and represents the more prevalent craniofacial malformation in humans, with an overall incidence of 1 out of 2000-3000 live births. Non-syndromic craniosynostoses (NSC) are believed to be multifactorial disorders, with a strong genetic component, due to possible gene–gene or gene–environment interactions that remain to be clearly identified. In this study we delved into the molecular signaling acting in calvarial tissue and cells from patients affected by nonsynodromic midline craniosynostosis, using a comparative analysis between fused and unfused sutures of each affected individuals. Using comparative microarray tissue gene expression profiling we have identified a subset of genes involved in the structure and function of the primary cilium, including the Bardet-Biedl syndrome 9 (BBS9) gene, which was recently associated to sagittal synostosis in a GWAS study. We therefore characterized BBS9 expression and cilium-related signaling in cells isolated from patients’ calvarial bone.

2018-05-31 | GSE79386 | GEO

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