Regeneration of skeletal muscle is dependent on the function of tissue-resident muscle stem cells (MuSC), known as satellite cells. MuSC dysfunction is central to muscle pathophysiology, including in age-associated loss of muscle regenerative capacity and congenital disorders such as Duchenne muscular dystrophy. Despite the central role of satellite cells in muscle regeneration, the signals controlling the balance between muscle stem cell quiescence, proliferation, and differentiation remain incompletely understood. Knowledge of the signals that maintain a quiescent state is particularly lacking, yet such cues are crucial to maintaining a stem cell reservoir that can meet the needs of regeneration throughout life. Here we identify Oncostatin M (OSM), a member of the interleukin-6 family of cytokines, as a potent and essential trans-acting regulator of satellite cell quiescence. Key to this discovery is the development of a novel in vivo imaging-based screening strategy allowing identification of proteins that do not induce in vitro proliferation, but instead maintain MuSCs in a non-mitotic state, poised for rapid robust expansion upon transplantation. We demonstrate that OSM induces reversible exit from the cell cycle and induction of a global transcriptional program significantly enriched within a newly established satellite cell quiescence signature. Genetic ablation of the OSM receptor in mice demonstrates that signaling via OSM/R is essential for maintenance of satellite cell quiescence, and for proper skeletal muscle regeneration in vivo. Given that aberrant activation and exhaustion of stem cells is seen in a variety of disorders, OSM constitutes an attractive therapeutic target in muscle disease states.
Induction of muscle stem cell quiescence by the secreted niche factor Oncostatin M.
Age, Specimen part
View SamplesStem cell differentiation is known to involve changes in RNA expression, but little is known about translational control during differentiation. We comprehensively profiled gene expression during differentiation of embryonic stem cells (ESCs) into embyroid bodies (EBs) by integrating conventional transcriptome analysis with global assessment of ribosome loading. Differentiation was accompanied by an anabolic switch, characterized by global increases in transcript abundance, polysome content, protein synthesis rates and protein content. Furthermore, 78% of expressed transcripts showed increased ribosome loading, thereby enhancing translational efficiency. Elevated protein synthesis was accompanied by enhanced phosphorylation of eIF-4E binding protein, suggesting regulation by the mTOR pathway.
A hierarchical network controls protein translation during murine embryonic stem cell self-renewal and differentiation.
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View SamplesGoal of the experiment: Analysis of gene expression changes in the cortex, striatum, hippocampus, hypothalamus, Drd2-MSNs and Drd1-MSNs of mice with a postnatal, neuron-specific ablation of GLP or G9a as compared to control mice.
Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex.
Specimen part
View SamplesWe have discovered rifampicin as a glycation inhibitor, which increases life span in C elegans. In order to understand the mechanism of rifampicin action, microarray analysis was performed to study the changes in gene expression brought about by the drug.
Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans.
Specimen part
View SamplesBackground: To define changes in gene expression from stem cells and early progenitor cells lacking histone deacetylase 3 (Hdac3), we purified bone marrow Lineage Negative, Sca1/cKit positive and Flt3 negative cells from wild type and Vav-Cre/Hdac3Flox/- mice. These lineage-specific knock out mice lack Hdac3 throughout the hematopoietic system. To ensure that only cells lacking Hdac3 were measured, we used a Lox-STOP-Lox-ROSA26-GFP transgene such that any cell containing active Cre also expresses GFP.
HDAC3 is essential for DNA replication in hematopoietic progenitor cells.
Specimen part
View SamplesThis study identifies miR-198 as a potential inhibitor of keratinocyte migration in skin
'See-saw' expression of microRNA-198 and FSTL1 from a single transcript in wound healing.
Specimen part, Time
View SamplesWe sought to determine genes whose expression changed upon treatment with a selective inhibitor of class I PI3 kinase.
Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models.
Cell line
View SamplesCocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. We identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region. To identify whether changes in H3K9me2 correlated with genome-wide alterations in gene expression in the NAc, we employed microarray analyses to examine gene expression profiles induced by a challenge dose of cocaine in animals with or without a history of prior cocaine exposure. Animals that had received repeated cocaine displayed dramatically increased gene expression 1 hour after a cocaine challenge in comparison to acutely treated animals. This increased gene expression still occurred in response to a cocaine challenge given after 1 week of withdrawal from repeated cocaine. These data suggest that repeated, but not acute, cocaine exposure results in persistent sensitized genomic responses to a cocaine challenge, indicating that sensitized behavioral responses to repeated cocaine are likely the result of G9a-dependent alterations in global transcriptional responses to cocaine.
Essential role of the histone methyltransferase G9a in cocaine-induced plasticity.
Specimen part
View SamplesThe majority of sporadic colorectal cancer cases are initiated by mutations in the APC tumor suppressor gene leading to constitutive activation of the Wnt/b-catenin signaling pathway and adenoma formation. Several pre-clinical models carrying germline mutations in the endogenous mouse Apc tumor supressor gene have been generated and their phenotype characterized. The predisposition of these mouse models to multiple intestinal adenomas closely resembles the FAP phenotype at the molecular, cellular and phenotypic level and may prove valuable to elucidate the molecular and cellular mechanisms underlying colorectal tumorigenesis. The goal of this study is to establish an expression signature characteristic of intestinal tumors characterized by the inactivation of Apc.
Cross-species comparison of human and mouse intestinal polyps reveals conserved mechanisms in adenomatous polyposis coli (APC)-driven tumorigenesis.
Sex, Age, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
A multi-omic analysis reveals the regulatory role of CD180 during the response of macrophages to Borrelia burgdorferi.
Age, Specimen part, Treatment
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