Myf6/MRF4 Mediated Myokine Signaling is Required for the Maintenance of the Adult Skeletal Muscle Stem Cell Pool
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA510349 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8329190.fastq.gz | Fastqsanger.gz | |||
| SRR8329191.fastq.gz | Fastqsanger.gz | |||
| SRR8329192.fastq.gz | Fastqsanger.gz | |||
| SRR8329193.fastq.gz | Fastqsanger.gz | |||
| SRR8329194.fastq.gz | Fastqsanger.gz |
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Project description:In metazoans, skeletal muscle evolved to contract and to produce force. Recent experimental evidence suggests, however, that skeletal muscle has also acquired endocrine functions and produces a vast array of myokines, but how myokine production is regulated and how they affect the resident stem cell population of the skeletal muscle is unknown. Here, we show that in adult skeletal muscle, Myf6/MRF4 is a major regulator of myokine expression. Genetic deletion of Myf6 in skeletal muscles leads to exhaustion of the muscle stem cell (MuSCs) pool in adult mice in a myokine-dependent manner but, surprisingly, does not disrupt muscle differentiation. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 is essential for the transcriptional activation of many myokines and muscle-secreted proteins, including ligands for canonical signaling pathways such as EGFR, VEGFR and STAT3. Consequently, MuSCs from Myf6 knockout animals show impaired activation of those signaling pathways and exhibit impaired quiescence, defective self-renewal, but nevertheless undergo differentiation. Lastly, we show that induction of myokine expression during aerobic and anaerobic exercise closely correlates with Myf6 expression. Together, these findings indicate that control of myokine signaling by Myf6 is critical to maintain muscle stem cell pool in adult skeletal muscle.
2020-09-18 | GSE123836 | GEO
Project description:In metazoans, skeletal muscle evolved to contract and produce force. Recent experimental evidence, however, suggests that skeletal muscle has also acquired endocrine functions and produces a vast array of muscle-derived cytokines and growth factors, collectively called myokines. The mechanisms that regulate myokine production and their effect on the resident stem cell population inskeletal muscle remain unknown. Here, we report that in adult skeletal muscle, Myf6/MRF4 is a major regulator of myokine expression. Genetic deletion of Myf6 in skeletal muscle leads to reduction of the muscle stem cell (MuSCs) pool in adult mice in a myokine-dependent manner but, surprisingly, does not disrupt muscle differentiation. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 is a direct regulator of many myokines and muscle-secreted proteins, including ligands for canonical signaling pathways such as EGFR and VEGFR. Consequently, in Myf6-deficient animals,MuSCs increasingly break quiescence, but can nevertheless undergo differentiation. Lastly, we show that Myf6 and its gene network rapidly respondto aerobic and anaerobic exercise. Together, these findings indicate that control of myokine signaling by Myf6 is critical to maintain muscle stem cell pool and skeletal muscle function via myokine signaling.
2020-10-02 | GSE133505 | GEO
Project description:The function and maintenance of muscle stem cells (MuSCs) are tightly regulated by signals originating from their niche environment. Skeletal myofibers are a principle component of the MuSC niche and are in direct contact with the muscle stem cells. Here, we show that Myf6 establishes a ligand/receptor interaction between muscle stem cells and their associated muscle fibers. Our data show that Myf6 transcriptionally regulates a broad spectrum of myokines and muscle-secreted proteins in skeletal myofibers, including EGF. EGFR signaling blocks p38 MAP kinase-induced differentiation of muscle stem cells. Homozygous deletion of Myf6 causes a significant reduction in the ability of muscle to produce EGF, leading to a deregulation in EGFR signaling. Consequently, although Myf6-knockout mice are born with a normal muscle stem cell compartment, they undergo a progressive reduction in their stem cell pool during postnatal life due to spontaneous exit from quiescence. Taken together, our data uncover a novel role for Myf6 in promoting the expression of key myokines, such as EGF, in the muscle fiber which prevents muscle stem cell exhaustion by blocking their premature differentiation.
| S-EPMC7726801 | biostudies-literature
Project description:Background: Proliferation is an important hallmark of cancer development and progression. Tumor growth rate significantly influences the course of the disease, and patients with tumors that have a high proliferation rate have an increased risk (10-20%) of metastasis and death. The genomic region encoding the transcription factor MYF6 is often altered in breast cancer, and alterations in MYF6 methylation have been linked to several different cancer types. However, the functional role of MYF6 in cancer remain unknown. Here, we have dissected the functional role of MYF6 in ER+ breast cancer. Methods: We analyzed cancer cell growth, proliferation, apoptosis, in vivo tumor formation, EMT phenotype and BCSC propagation in MCF7 and T47D ER+ breast cancer models with inducuble MYF6 overexpression or MYF6 knockdown. Additionally, we performed detailed molecular profiling and network analysis, and Western blot validation of identified targets. Results: We show that MYF6 suppresses PI3K/Akt/mTOR and Wnt pathway signaling, two important pathways of cell proliferation, and suppression was accompanied by reduced cell growth in vitro and in vivo, and G0/G1 phase cell cycle arrest. MYF6 also induced an EMT phenotype and forced the cells into a cancer stem cell-like state, leading to resistance to -irradiation. Network analysis of molecular profiling data revealed that MYF6 activates hypoxia signaling and HIF1A was identified as a downstream target and an upstream regulator of MYF6. Conclusion: Our results suggest both a tumor-suppressive and oncogenic role of MYF6 in ER+ breast cancer, and we theorize that, subject to the presence or absence of yet unidentified cellular factors, MYF6 can switch from a growth-inhibiting tumor suppressor to an oncogene state, associated with cancer stem cells and treatment resistance.
2023-01-31 | GSE188537 | GEO
Project description:Background: Proliferation is an important hallmark of cancer development and progression. Tumor growth rate significantly influences the course of the disease, and patients with tumors that have a high proliferation rate have an increased risk (10-20%) of metastasis and death. The genomic region encoding the transcription factor MYF6 is often altered in breast cancer, and alterations in MYF6 methylation have been linked to several different cancer types. However, the functional role of MYF6 in cancer remain unknown. Here, we have dissected the functional role of MYF6 in ER+ breast cancer. Methods: We analyzed cancer cell growth, proliferation, apoptosis, in vivo tumor formation, EMT phenotype and BCSC propagation in MCF7 and T47D ER+ breast cancer models with inducuble MYF6 overexpression or MYF6 knockdown. Additionally, we performed detailed molecular profiling and network analysis, and Western blot validation of identified targets. Results: We show that MYF6 suppresses PI3K/Akt/mTOR and Wnt pathway signaling, two important pathways of cell proliferation, and suppression was accompanied by reduced cell growth in vitro and in vivo, and G0/G1 phase cell cycle arrest. MYF6 also induced an EMT phenotype and forced the cells into a cancer stem cell-like state, leading to resistance to -irradiation. Network analysis of molecular profiling data revealed that MYF6 activates hypoxia signaling and HIF1A was identified as a downstream target and an upstream regulator of MYF6. Conclusion: Our results suggest both a tumor-suppressive and oncogenic role of MYF6 in ER+ breast cancer, and we theorize that, subject to the presence or absence of yet unidentified cellular factors, MYF6 can switch from a growth-inhibiting tumor suppressor to an oncogene state, associated with cancer stem cells and treatment resistance.
2023-01-31 | GSE188505 | GEO
Project description:Maintenance and self-renewal of the spermatogonial stem cell (SSC) population is the cornerstone of male fertility. In this manuscript we have identified a key role for the nucleosome remodelling protein Chromodomain Helicase DNA binding protein 4 (CHD4) in regulating SSC function. Gene expression analyses revealed that CHD4 expression is largely restricted to spermatogonia in the mouse testis, and is particularly enriched in SSCs. Using spermatogonial transplantation techniques and RNAi mediated knockdown it was established that loss of Chd4 expression significantly impairs SSC regenerative capacity, resulting in a ~50% reduction in colonisation of recipient testes. A single cell RNA-seq comparison depicted reduced expression of ‘self-renewal’ genes such as Gfra1 and Pten following Chd4 knockdown, along with increased expression of signature progenitor genes, Neurog3 and Dazl. Co-immunoprecipitation analyses demonstrated that CHD4 regulates gene expression in spermatogonia not only though its traditional association with the remodelling complex NuRD, but also via interaction with the GDNF-responsive transcription factor SALL4. Cumulatively, the results of this study depict a previously unappreciated fundamental role for CHD4 in controlling fate decisions in the spermatogonial pool.
2021-06-17 | PXD022066 | Pride
Project description:Acetyl-CoA is a Key Molecule for Nephron Progenitor Cell Pool Maintenance
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Project description:A regulatory role for CHD4 in maintenance of the spermatogonial stem cell pool
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Project description:Mrf4 (Myf6) is a member of the basic helix-loop-helix (bHLH) myogenic regulatory transcription factor (MRF) family, which also contains Myod, Myf5 and myogenin. Mrf4 is implicated in commitment of amniote cells to skeletal myogenesis and is also abundantly expressed in many adult muscle fibres. The specific role of Mrf4 is unclear both because mrf4 null mice are viable, suggesting redundancy with other MRFs, and because of genetic interactions at the complex mrf4/myf5 locus. We report the cloning and expression of an mrf4 gene from zebrafish, Danio rerio, which shows conservation of linkage to myf5. Mrf4 mRNA accumulates in a subset of terminally differentiated muscle fibres in parallel with myosin protein in the trunk and fin. Although most, possibly all, trunk muscle expresses mrf4, the level of mRNA is dynamically regulated. No expression is detected in muscle precursor cell populations prior to myosin accumulation. Moreover, mrf4 expression is not detected in head muscles, at least at early stages. As fish mature, mrf4 expression is pronounced in the region of slow muscle fibres.
| S-EPMC3001336 | biostudies-literature
Project description:The factors necessary to maintain organ-specific progenitor cells are poorly understood and yet of extreme clinical importance. Here, we identify the transcription factor SOX9 as the first specific marker and maintenance factor of multipotential progenitors during pancreas organogenesis. In the developing pancreas, SOX9 expression is restricted to a mitotically active, Notch-responsive subset of PDX1(+) pluripotent progenitors and is absent from committed endocrine precursors or differentiated cells. Similar to Notch mutations, organ-specific Sox9 inactivation in mice causes severe pancreatic hypoplasia resulting from depletion of the progenitor cell pool. We show that Sox9 maintains pancreatic progenitors by stimulating their proliferation, survival, and persistence in an undifferentiated state. Our finding that SOX9 regulates the Notch-effector HES1 suggests a Notch-dependent mechanism and establishes a possible genetic link between SOX factors and Notch. These findings will be of major significance for the development of in vitro protocols for cell replacement therapies.
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