RNA-seq analysis to profile TGF-beta/Activin signaling-dependent gene expression in Drosophila larval skeletal muscle
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ABSTRACT:
PROVIDER: PRJNA683069 | ENA |
REPOSITORIES: ENA
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Project description:We performed RNA-seq analysis to identify genes whose expression is regulted or influenced by TGF-beta/Activin signaling in Drosophila larval skeletal muscle. We used two sample sets. One is composed of wild-type and smox (the sole R-smad of TGF-beta/Activin signaling in Drosophila). The other is composed of control and larvae of muscle-specific expression of activated Baboo (Type I receptor). By comparing differential expressions from these two sets, we were able to identify genes whose expression is regulated by TGF-beta/Activin pathway in the skeletal muscle of Drosophila larvae.
2020-12-08 | GSE162810 | GEO
Project description:Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-β1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.
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Project description:Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a non-canonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the pro-tumoral role of KMT2D loss. These findings support a tumor-suppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.
2023-03-31 | GSE199856 | GEO
Project description:Physical training improves insulin sensitivity and can prevent type 2 diabetes. However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response is also a potent regulator of microRNAs (miRs). Aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation and the induction of extracellular matrix components, and identified several TGF-β1-regulated miRs. qPCR validated a potent upregulation of miR143/145 and miR181a2 by TGF-β1 in both human myoblasts and differentiating myotubes. Human skeletal muscle biopsy donors participating in a supervised 8-week endurance training intervention (n=40) were categorized as responder based on fold change ISIMats (≥ +1.1) or low responder. In skeletal muscle of low responders, TGF-β signaling and miR143/145 levels were stronger induced by training than in responders. Target-mining revealed HDACs, MYHs and insulin signaling components INSR and IRS1 as potential miR143/145 targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR143/145 targets. Elevated TGF-β signaling and miR143/145 induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: By negatively impacting cell fusion and myofiber functionality via miR143 suppressing its novel targets MYH1/4; by directly impairing insulin signaling via reduction of INSR by TGF-β and fine-tuned IRS1 suppression by miR143.
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Project description:Among the physiological consequences of extended space flight are loss of skeletal muscle and bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis is that regulated by the secreted signaling proteins, myostatin and activin A. Here, we used both pharmacological and genetic approaches to investigate the effect of targeting myostatin/activin A signaling in mice that were sent to the International Space Station. We show that inhibition of myostatin/activin A signaling has a significant protective effect against microgravity-induced muscle and bone loss. These findings have implications for therapeutic strategies to combat the concomitant muscle and bone loss occurring in people afflicted with disuse atrophy on Earth as well as in astronauts in space, especially during prolonged missions.
2020-09-16 | GSE156321 | GEO
Project description:Physical training improves insulin sensitivity and can prevent type 2 diabetes. However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response is also a potent regulator of microRNAs (miRs). Aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation and the induction of extracellular matrix components, and identified several TGF-β1-regulated miRs. qPCR validated a potent upregulation of miR143/145 and miR181a2 by TGF-β1 in both human myoblasts and differentiating myotubes. Human skeletal muscle biopsy donors participating in a supervised 8-week endurance training intervention (n=40) were categorized as responder based on fold change ISIMats (≥ +1.1) or low responder. In skeletal muscle of low responders, TGF-β signaling and miR143/145 levels were stronger induced by training than in responders. Target-mining revealed HDACs, MYHs and insulin signaling components INSR and IRS1 as potential miR143/145 targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR143/145 targets. Elevated TGF-β signaling and miR143/145 induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: By negatively impacting cell fusion and myofiber functionality via miR143 suppressing its novel targets MYH1/4; by directly impairing insulin signaling via reduction of INSR by TGF-β and fine-tuned IRS1 suppression by miR143.
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Project description:Skeletal muscle injury-responsive macrophage subsets in larval zebrafish
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Project description:Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastasis spread. Signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming grow factor (TGF)- is a recognized suppressor of NK cells that inhibits IL-15 dependent signaling events and induces cellular transdifferentiation, however the role of other SMAD signaling pathways in NK cells is unknown. We used a global, label-free proteomics approach to compare the protein expression profiles of NK cells in the presence of TGF-b or activin-A.
2020-04-06 | PXD011672 | Pride
Project description:Single-cell RNA-sequencing (scRNA-seq) was applied to identify and characterise macrophage subsets that responded to larval zebrafish muscle injury. The Tg(mpeg1:mCherry) transgenic zebrafish line was utilised to isolate mCherry-expressing macrophages by FACS. Following needle-stab muscle injury of a 4 days post fertilisation (dpf) larvae, the wound site was dissected out at 1, 2, and 3 days post injury (dpi) for macrophage isolation. Macrophages isolated from 4 dpf-uninjured larvae were also included. This analysis led to the identification of 8 discrete clusters of macrophages, one of which corresponded to uninjured macrophages. The 7 wound-present macrophage subsets highlighted greater macrophage heterogeneity than previously described in an in vivo skeletal muscle injury context.
2020-12-11 | GSE162979 | GEO
Project description:Inhibition of the myostatin signaling pathway is emerging as a promising therapeutic means to treat muscle wasting disorders. Activin type IIB receptor is the putative myostatin receptor, and a soluble activin receptor (ActRIIB-Fc) has been demonstrated to potently inhibit a subset of TGF-β family members including myostatin. In order to determine reliable and valid biomarkers for myostatin pathway inhibition, we assessed gene expression profiles for quadriceps muscles from mice treated with ActRIIB-Fc compared to mice genetically lacking myostatin and control mice.
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