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BMP4 and BMP6 stimulation of adult mouse muscle stem cells activates the Notch signaling pathway [RNA-seq I]

ABSTRACT: Muscle stem cell (MuSC) activation, proliferation, self-renewal, and differentiation are tightly regulated processes that enable muscle development and regeneration without exhaustion of the stem cell pool. BMP signaling keeps MuSCs in a proliferative state and prevents their differentiation. We investigated the effect of bone morphogenetic protein 4 and 6 (BMP4 and BMP6) on transcriptional regulation and intracellular signaling of adult murine MuSCs using RNA-sequencing, RNA expression arrays, pathway-specific qPCR arrays, and Cleavage Under Targets and Tagmentation (CUT&Tag), which identifies the binding sites of transcription factors and the presence of specific histone marks with high spatial resolution. Freshly isolated MuSCs were grown for 42 to 72 hours, kept serum deprived for 6 hours, and then stimulated with BMP4/6. BMP4/6 addition resulted in a rapid increase in Inhibitor of DNA binding 1 (Id1)-expression, a typical BMP target gene, which peaked after one hour. As expected, stimulation with BMP4/6 resulted in a significant increase in transcription of BMP target genes such as Smad7, Nog, Id1, Klf10, and Lif, but also a strong increase in transcription of Notch pathway genes such as Hes1, Lfng, and Hey1. We showed that the important BMP pathway effectors SMAD4 and pSMAD1/5/9 bind to the promoters of these Notch targets. Our results suggest that the rapid expression of genes encoding Notch signaling components is due to direct regulation by BMP signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE159594 | GEO | 2023/10/01

REPOSITORIES: GEO

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BMP4 and BMP6 stimulation of adult mouse muscle stem cells activates the Notch signaling pathway [array]

Project description:Muscle stem cell (MuSC) activation, proliferation, self-renewal, and differentiation are tightly regulated processes that enable muscle development and regeneration without exhaustion of the stem cell pool. BMP signaling keeps MuSCs in a proliferative state and prevents their differentiation. We investigated the effect of bone morphogenetic protein 4 and 6 (BMP4 and BMP6) on transcriptional regulation and intracellular signaling of adult murine MuSCs using RNA-sequencing, RNA expression arrays, pathway-specific qPCR arrays, and Cleavage Under Targets and Tagmentation (CUT&Tag), which identifies the binding sites of transcription factors and the presence of specific histone marks with high spatial resolution. Freshly isolated MuSCs were grown for 42 to 72 hours, kept serum deprived for 6 hours, and then stimulated with BMP4/6. BMP4/6 addition resulted in a rapid increase in Inhibitor of DNA binding 1 (Id1)-expression, a typical BMP target gene, which peaked after one hour. As expected, stimulation with BMP4/6 resulted in a significant increase in transcription of BMP target genes such as Smad7, Nog, Id1, Klf10, and Lif, but also a strong increase in transcription of Notch pathway genes such as Hes1, Lfng, and Hey1. We showed that the important BMP pathway effectors SMAD4 and pSMAD1/5/9 bind to the promoters of these Notch targets. Our results suggest that the rapid expression of genes encoding Notch signaling components is due to direct regulation by BMP signaling.

2023-10-01 | GSE127798 | GEO

Operation of the atypical canonical BMP signaling pathway during human odontogenesis

Project description:BMP (bone morphogenetic protein) signaling plays essential roles in the regulation of early tooth development. It is well acknowledged that with binding of extracellular BMP ligands to the type I and type II transmembrane serine/threonine kinase receptor complexes when triggering of the BMP canonical signaling pathway, receptor activated Smad1/5/8 in cytoplasm bind to Smad4, the central mediator of the canonical BMP signaling pathway, to form transfer complexes for entering the nucleus and regulating target gene expression. However, our recent studies reveal the functional operation of a novel BMP mediated signaling pathway named as the atypical BMP canonical signaling pathway in mouse developing tooth, which is Smad1/5/8 dependent but Smad4 independent. In the current study, we investigated whether this atypical BMP canonical signaling is conserved in human odontogenesis. We showed that pSmad1/5/8 is required for expression of MSX1, a well-defined BMP signaling target gene, in human dental mesenchyme, but the typical BMP canonical signaling is indeed not operating in the early human developing tooth, as assessed by the absence of pSMAD1/5/8-SMAD4 complexes in the dental mesenchyme and expression of MSX1 and translocation of pSMAD1/5/8 induced by BMP4 protein is SMAD4-independent in dental mesenchymal cells. Moreover, RNA-Seq data sets comparing the transcriptome profiles of human dental mesenchymal cells with and without SMAD4 knockdown by siRNA displays unchanged expression profiles of pSMAD1/5/8 downstream target genes, further affirming the functional operation of the atypical canonical BMP signaling pathway in a manner of SMAD1/5/8-dependent but SMAD4-independent in the dental mesenchyme during early odontogenesis.

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Liver expression of Bmp6, Smad7, Id1 and Atoh8 is regulated by iron stores

Project description:Background & Aims: Although hepcidin expression was shown to be induced by the BMP signaling pathway, it is not yet known how iron regulates hepcidin and which of the BMP molecules is the endogenous regulator of iron homeostasis in vivo. We therefore assessed liver transcription profiles of mice fed an iron-deficient or an iron-enriched diet and looked for genes that were regulated similarly to hepcidin in that context. Methods: Genome-wide liver expression profiles of mice of the B6 and D2 genetic backgrounds subjected to iron-deficient, -balanced, or -enriched diets were obtained using Agilent Whole Genome microarrays. Real-time quantitative-PCR and western-blots were used to confirm microarray results and compare gene expression variations induced by secondary iron deficiency or iron overload with those consecutive to Smad4 or Hamp1-deficiency. Results: Among 1419 transcripts significantly modulated by the dietary iron content, four were regulated similarly to the hepcidin genes Hamp1 and Hamp2. They are coding for Bmp6, the regulator of Bmp/Smad signal transduction Smad7, the negative regulator of basic helix-loop-helix (bHLH) proteins Id1, and a protein with a bHLH domain, Atoh8. The iron overload developed by Smad4 and Hamp1-deficient mice also increased Bmp6 transcription. Body iron stores influence Smad1/5/8 phosphorylation and, as shown by analysis of mice with liver-specific disruption of Smad4, the binding partner for the receptor-activated Smads is necessary for activation of Smad7, Id1, and Atoh8 transcription by iron. Conclusions: Liver expression of Bmp6, Smad7, Id1, and Atoh8 is regulated by body iron stores and may participate in hepcidin regulation through the Bmp/Smad pathway. Keywords: response to dietary iron content

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Project description:The canonical bone morphogenetic protein (BMP) signaling pathway plays a crucial regulatory role in tooth development by activating Smad proteins to regulate gene expression. We previously identified an atypical canonical BMP signaling in dental mesenchyme that is Smad4-independent but Smad1/5-dependent. This study demonstrates that phosphorylated Smad1/5 (pSmad1/5) and Smad4 regulate distinct gene sets in dental mesenchyme. Real-time monitoring of BMP-Smad transcriptional activity revealed that Smad4-dependent canonical BMP signaling is restricted to neurovascular cells surrounding the condensed dental mesenchymal cells where pSmad1/5 is present. Notably, pSmad1/5 in dental mesenchymal cells form complexes with pSmad3 to prevent canonical BMP signaling. CUT&RUN assays revealed genome-wide co-occupancy of pSmad1/5 and pSmad3, indicating their function as transcriptional regulation units. Integrative analyses demonstrated that this atypical canonical BMP signaling regulates tooth sensory innervation and maintains odontogenic inductive potential in dental mesenchyme, enabling the identification of critical genes for maintaining tooth inductive capability. Our findings elucidate the operating mechanism of atypical canonical BMP signaling in dental mesenchymal cells and clarify how BMP-Smad signaling exerts diverse functions across different cell types, informing future tooth bioengineering strategies.

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Distinct BMP-Smad Signaling Outputs Confer Diverse Functions in Dental Mesenchyme [CUT&Run]

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Distinct BMP-Smad Signaling Outputs Confer Diverse Functions in Dental Mesenchyme [ChIP-seq]

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BMP4 and BMP6 stimulation of adult mouse muscle stem cells activates the Notch signaling pathway

Project description:BMP4 and BMP6 stimulation of adult mouse muscle stem cells activates the Notch signaling pathway

| PRJNA1310614 | ENA

BMP4 triggers regulatory circuits specifying the cardiac mesoderm lineage

Project description:Cardiac lineage specification in the mouse is controlled by TGFβ and WNT signaling. From fly to fish, BMP has been identified as an indispensable heart inducer. A detailed analysis of the role of Bmp4 and its effectors Smad1/5, however, was still missing. We show that Bmp4 induces cardiac mesoderm formation in murine embryonic stem cells in vitro. Bmp4 first activates Wnt3 and upregulates Nodal. pSmad1/5 and the WNT effector Tcf3 form a complex, and together with pSmad2/3 activate mesoderm enhancers and Eomes. They then cooperate with Eomes to consolidate the expression of many mesoderm factors, including T. Eomes and T form a positive feedback loop and open additional enhancers regulating early mesoderm genes, including the transcription factor Mesp1 establishing the cardiac mesoderm lineage. In parallel, the neural fate is suppressed. Our data confirm the pivotal role of Bmp4 in cardiac mesoderm formation in the mouse. We describe in detail the consecutive and cooperative actions of three signaling pathways, BMP, WNT and Nodal, and their effector transcription factors, during cardiac mesoderm specification.

2023-05-03 | GSE168580 | GEO

BMP4 and BMP6 stimulation of adult mouse muscle stem cells activates the Notch signaling pathway [array]

Project description:BMP4 and BMP6 stimulation of adult mouse muscle stem cells activates the Notch signaling pathway [array]

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Vitamin D opposes multilineage cell differentiation induced by Notch inhibition and BMP pathway activation in human colon organoids

Project description:Understanding the mechanisms involved in colonic epithelial differentiation is key to unraveling the alterations causing inflammatory conditions and cancer. Organoid cultures provide a unique tool to address these questions but studies are scarce. We report a differentiation system toward enterocytes and goblet cells, the two major colonic epithelial cell lineages, using organoids from human healthy tissue. Culture of normal patient-derived colon organoids in medium lacking stemness agents resulted in a modest ultrastructural differentiation phenotype with low-level expression of enterocyte (KLF4, KRT20, CA1) and goblet cell (TFF2, TFF3, AGR2) lineage markers. BMP pathway activation through depletion of Noggin and addition of BMP4 resulted in enterocyte-biased differentiation. Contrarily, blockade of the Notch pathway using the g-secretase inhibitor dibenzazepine (DBZ) favored goblet cell differentiation. Combination treatment with BMP4 and DBZ caused a balanced strong induction of both lineages. In contrast, colon tumor organoids responded poorly to BMP4 and DBZ showing only weak signals of cell differentiation. We also investigated the effects of 1α,25-dihydroxyvitamin D3 (calcitriol) on differentiation. Calcitriol attenuated the effects of the BMP4 and DBZ on normal colon organoids, with reduced expression of differentiation genes and phenotype. Consistently, in normal organoids, calcitriol inhibited early signaling by BMP4 as assessed by reduction of the level of phospho-SMAD1/5/8. Our results show that BMP and Notch signaling play key roles in human colon stem cell differentiation to the enterocytic and goblet cell lineages and that calcitriol modulates these processes favoring stemness features.

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