Muscle injury causes long-term changes in stem cell DNA methylation [RRBS]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE143890 | GEO | 2022/12/01
REPOSITORIES: GEO
Similar Datasets
Project description:Injury to muscle brings about the activation of stem cells, which then generate new myocytes to replace the damaged tissue. We now demonstrate that this activation causes a dramatic change in the stem cell methylation pattern that prepares them epigenetically for terminal myocyte differentiation. These demethylation and de novo methylation events occur at regulatory elements associated with genes involved in myogenesis. Local injury of one muscle brings about an almost identical epigenetic change in satellite cells from other muscles in the body, as well. Furthermore, this same methylation state is also generated in muscle stem cells of female animals following full-term pregnancy, even in the absence of any injury. In all of these cases, which appear to be mediated by circulating factors, the new methylation profile is then stably maintained in resident muscle stem cells and thus represents a molecular memory of previous physiological events that is probably programmed to provide a mechanism for adapting to the environment. Here we show the changes in gene expression that accompany the changes in DNA methylation.
2022-12-01 | GSE142111 | GEO
Project description:MicroRNA expression profiling during muscle stem cell activation. Quiescent muscle stem cells from uninjured muscles and activated muscle stem cells from injured muscles at indicated time points were isolated by FACS. MicroRNA expression profiling during muscle stem cell activation using real-time PCR based miRNA arrays. Muscle stem cells were harvested at indicated time points (0hr, 36hr, 60hr and 72hr) after injury. 3 technical replicates were performed. Supplementary files: Raw data (Ct) and complete processed data (dCt, ddCt, fold-change) by platform.
2012-01-01 | E-GEOD-26780 | biostudies-arrayexpress
Project description:Muscle stem cells, also known as satellite cells, are largely non-proliferative in uninjured skeletal muscle but transition at sites of injury into rapidly dividing progenitors that mediate muscle repair. As early events in satellite cell activation are rate-limiting for recovery from muscle damage, there is substantial interest in discovering their molecular driver(s). Using a comparative transcriptomic approach, we identified a prominent Fos signature in recently activated muscle satellite cells, which was rapidly and transiently induced by muscle damage. Functional interrogation using complementary genetic mouse models revealed that FOS is required for efficiently initiating key stem cell functions, including cell cycle entry, stem/progenitor cell expansion, and regeneration of muscle after injury. Transcriptional profiling further revealed that FOS activates critical gene circuits that stimulate cell migration, proliferation, and differentiation while simultaneously repressing quiescence-promoting gene signatures. Pharmacological and genetic disruption of one of these FOS-activated target genes, mono-ADP Ribosyl-Transferase 1 (Art1), in freshly isolated satellite cells substantially diminished cell cycle entry and expansion of the pool of regenerative stem cells. Together, these data implicate FOS as a crucial inducer of early-acting, pro-regenerative gene targets and highlight new transcriptional and post-translational modification events necessary for optimal injury-activated muscle stem cell regenerative responses.
2021-01-27 | GSE119895 | GEO
Project description:Muscle stem cells, also known as satellite cells, are largely non-proliferative in uninjured skeletal muscle but transition at sites of injury into rapidly dividing progenitors that mediate muscle repair. As early events in satellite cell activation are rate-limiting for recovery from muscle damage, there is substantial interest in discovering their molecular driver(s). Using a comparative transcriptomic approach, we identified a prominent Fos signature in recently activated muscle satellite cells, which was rapidly and transiently induced by muscle damage. Functional interrogation using complementary genetic mouse models revealed that FOS is required for efficiently initiating key stem cell functions, including cell cycle entry, stem/progenitor cell expansion, and regeneration of muscle after injury. Transcriptional profiling further revealed that FOS activates critical gene circuits that stimulate cell migration, proliferation, and differentiation while simultaneously repressing quiescence-promoting gene signatures. Pharmacological and genetic disruption of one of these FOS-activated target genes, mono-ADP Ribosyl-Transferase 1 (Art1), in freshly isolated satellite cells substantially diminished cell cycle entry and expansion of the pool of regenerative stem cells. Together, these data implicate FOS as a crucial inducer of early-acting, pro-regenerative gene targets and highlight new transcriptional and post-translational modification events necessary for optimal injury-activated muscle stem cell regenerative responses.
2021-01-27 | GSE119695 | GEO
Project description:Organ metabolism is spatio-temporally regulated at the cellular and tissue level to link metabolic pathways with key homeostatic processes, but little is known about the cellular regulation of metabolism during tissue repair after acute injury. In a murine model of ischemic cardiac injury, we demonstrate that the cardiac muscle cell regulates pyrimidine biosynthesis of non-muscle cells to affect cardiac repair. We demonstrate that the ectonucleotidase ENPP1 hydrolyzes extracellular ATP released after cardiac injury to form AMP, which then induces the cardiomyocyte to release adenine and specific ribonucleosides that disrupt pyrimidine biosynthesis, cause genotoxic stress and induce a p53 mediated cell death of non-myocyte cells such as fibroblasts, macrophages, endothelial and smooth muscle cells. As non-myocyte cells play a critical role in mediating heart repair, we demonstrate that rescue of pyrimidine biosynthesis by administration of uridine after cardiac injury or by genetic targeting of ENPP1/AMP pathway enhances repair and post infarct heart function. We establish a high through- put assay to screen a large library of small molecules to identify small molecule ENPP1 inhibitors and demonstrate that systemic administration of ENPP1 inhibitors following heart injury rescues pyrimidine biosynthesis in non-myocyte cells and augments tissue repair and function. We determine specific biochemical steps of pyrimidine biosynthesis that are disrupted and identify the critical pyrimidine metabolite orotidine as a serum biomarker for monitoring the metabolic control of tissue repair. These observations demonstrate that the cardiac muscle cell by releasing adenine regulates pyrimidine metabolism in non-muscle cells via paracrine mechanisms and provide insight into how inter-cellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.
2021-11-03 | GSE185060 | GEO
Project description:Interestingly, the DMP1 cre Mbtps1 knockout mice do not demonstrate a noticeable bone phenotype despite gene expression changes. Only change was in bone stiffness. However, muscles from DMP1 cre Mbtps1 knockout mice did show a phenotype: changes in contractile force (increased); changes in myosin heavy chain expression, and an increase in myocyte regeneration evidenced by centralized nuclei in type I myosin heavy chain expressing cells. As a result, we wanted to know if these physiological changes were accompanied by changes in gene expression. We found that a number of genes were increased---including those associated with improved muscle performance and with activation of satellite cells, e.g., muscle stem cells. These changes in gene expression support our hypothesis which is that the bone (osteocytes) signal a change in muscle function via a cross-talk mechanism.
2015-12-29 | GSE69985 | GEO
Project description:Satellite cells are resident skeletal muscle stem cells responsible for muscle maintenance and repair. In resting muscle, satellite cells are maintained in a quiescent state. Satellite cell activation induces the myogenic commitment factor, MyoD, and cell cycle entry to facilitate transition to a population of proliferating myoblasts that eventually exit the cycle and regenerate muscle tissue. The molecular mechanism involved in the transition of a quiescent satellite cell to a transit-amplifying myoblast is poorly understood. We used microarrays to detail the global program of gene expression of in vivo satellite cell activation through muscle injury and identified RNA post-transcriptional regulation as a key component of satellite cell activation. Wild type or Sdc4-/- satellite cells were FACS isolated from resting muscle or from muscle 12h and 48h following barium chloride-induced muscle injury. 5000 cell equivalents of RNA was labeled and hybridized to MOE430v2 GeneChips (Affymetrix) and scanned as per manufacturers protocol. Probeset intensities were GCRMA normalized for further analysis including UPGMA hierarchical clustering, analysis of variance (ANOVA), and fold change.
2012-07-31 | E-GEOD-38870 | biostudies-arrayexpress
Project description:The aims of the experiment were to profile the cell types in the adult mouse cardiac interstitium (non-myocyte cells) and how they respond to myocardial infarction injury. Adult, male, Pdgfra +/GFP mice were subject to either a myocardial infarction or sham injury, with cells isolated from cardiac ventricles 3 or 7 days following surgery. We obtained scRNA-seq profiles of two cell fractions: total interstitial (non-myocyte) cell population (TIP) and FACS-sorted GFP+/Cd31- cells (GFP).
2019-03-28 | E-MTAB-7376 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) are important in the regulation of many biological processes including muscle development. However, little is known regarding miRNA regulation of muscle regeneration. In mature murine tibialis anterior muscle following injury, 298 miRNAs were significantly changed during the time course of muscle regeneration including 86 that were altered greater than 10-fold as compared to uninjured muscle. Temporal miRNA expression patterns were identified and included inflammation-related miRNAs (miR-223 and -147) that increased immediately after injury; this pattern contrasted to that of mature muscle-specific miRNAs (miR-1, -133a and -499) that were abruptly decreased following injury and then up-regulated in later regenerative events. Another cluster of miRNAs were transiently increased in the early days of muscle regeneration. This included miR-351, a miRNA that was also transiently expressed during myogenic progenitor cell (MPC) differentiation in vitro. Based on computational predictions, further studies demonstrated that E2f3 was a target of miR-351 in myoblasts. Moreover, knockdown of miR-351 expression inhibited MPC proliferation and promoted apoptosis during MPC differentiation, whereas miR-351 overexpression protected MPC from apoptosis during differentiation. Collectively, these observations suggest that miR-351 is involved in both the maintenance of MPC proliferation and the transition of MPC into differentiated myotubes. Thus, a novel, time-dependent sequence of molecular events during skeletal muscle regeneration has been identified, i.e., miR-351 inhibits E2f3 expression, a key regulator of cell cycle progression and proliferation, and promotes MPC proliferation and protects early differentiating MPC from apoptosis, important events in the hostile tissue environment after acute muscle injury. Skeletal muscles are damaged and repaired repeatedly throughout life. Muscle regeneration maintains locomotor function during aging and delays the appearance of clinical symptoms in neuromuscular diseases, such as Duchenne muscular dystrophy. The capacity for skeletal muscle growth and regeneration is conferred by satellite cells located between the basal lamina and the sarcolemma of mature myofibers. Upon injury, satellite cells reenter the cell cycle, proliferate, and then exit the cell cycle either to renew the quiescent satellite cell pool or to differentiate into mature myofibers. Despite recent advances, genes involved in these processes are still largely unknown. Understanding the molecular mechanisms that regulate satellite cell activities could promote development of novel countermeasures to enhance muscle regeneration that is compromised by diseases or aging. Using a muscle injury mouse model, we profiled miRNA expression during muscle regeneration.
2012-04-24 | E-GEOD-37479 | biostudies-arrayexpress
Project description:Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hyphertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload. Microarrays were used to identify specific genes that might be globally affected in the absence of c-jun in cardiomyocytes. Total RNA was extracted from the hearts of 10 weeks old Junf/f (n=2) and Jun delta mu (n=2) mice using TRIzol Reagent.
2013-09-19 | E-GEOD-47898 | biostudies-arrayexpress