Role of Prdm16 in fibro-adipogenic progenitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE148432 | GEO | 2021/06/02
REPOSITORIES: GEO
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Project description:Role of Prdm16 in fibro-adipogenic progenitors
| PRJNA624179 | ENA
Project description:In differentiated cells, inhibition of methyltransferases G9a and GLP eliminated H3K9me2 predominantly at A-type genomic compartments, and the remaining H3K9me2 marks were strongly associated with B-type compartments and lamina-associated domains (LADs). However, inhibition of G9a/GLP in mouse embryonic stem cells (ESCs) removed most of the H3K9me2 modifications in both A and B compartments. Furthermore, chemical inhibition of G9a/GLP in mouse hepatocytes decreased chromatin-nuclear lamina (NL) interactions, increased the degree of genomic compartmentalization and the boundary strength of topologically associating domains (TADs) between A and B compartments, and altered the expression of hundreds of genes that were associated with alterations of chromatin structure.
2021-06-20 | GSE132957 | GEO
Project description:The purpose of this study is to investigate how immune cells (macrophages) are closely linked with fibro-adipogenic progenitors (FAPs) during recovery processe. We report that the depletion of Mrc1+ (gene encoding CD206) M2-like macrophages promoted the recovery of muscle after injury. A total RNA sequence analysis of whole muscle or isolated FAPs revealed that the depletion of Mrc1+ M2-like macrophages resulted in the activation of FAPs. Activated FAPs secrete follistatin (Fst), a promyogenic factor, boosting the recovery process. We further determined that the knockdown of FAPs-derived Fst delayed the recovery process. Mechanistically, Mrc1+ M2-like macrophages-specific TGF-b1 inhibited the activation of FAPs, and the FAPs failed to secrete Fst.
2022-09-12 | GSE173555 | GEO
Project description:Fibro adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin- deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild type and mdx mice, suggest that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.
2019-06-24 | PXD014195 | Pride
Project description:In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis, while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues. Fibroadipocyte progenitors were isolated from wild-type and IL-4Ra knockout (IL-4Ra -/-) mice and were treated with vehicle or IL4 stimulation in culture prior to microarray analysis. 4 biological replicates of each condition were performed.
2013-04-11 | E-GEOD-44933 | biostudies-arrayexpress
Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration - is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an "HDAC-myomiR-BAF60 variant network" regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) miR-1.2, miR-133 and miR-206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. miRNA modulation upon Histone Deacetylase inhibition in Fibro-Adipogenic Progenitors (FAPs) derived from young mdx mice was evaluated by small RNA-sequencing in 2 controls and 2 treated samples
2014-04-23 | E-GEOD-51933 | biostudies-arrayexpress
Project description:Histone H3 lysine 9 dimethylation (H3K9me2) is a highly conserved silencing epigenetic mark. Chromatin marked with H3K9me2 forms large domains in mammalian cells and overlaps well with lamina-associated domains and the B compartment defined by Hi-C. However, the role of H3K9me2 in 3-dimensional (3D) genome organization remains unclear. We investigated genome-wide H3K9me2 distribution, transcriptome, and 3D genome organization in mouse embryonic stem cells following the inhibition or depletion of five H3K9 methyltransferases (MTases): G9a, GLP, SETDB1, SUV39H1, and SUV39H2. H3K9me2 was regulated by all five MTases; however, H3K9me2 and transcription in the A and B compartments were regulated by different MTases. H3K9me2 in A compartments was primarily regulated by G9a/GLP and SETDB1, while H3K9me2 in the B compartments was regulated by all five MTases. Furthermore, decreased H3K9me2 correlated with changes to the more active compartmental state that accompanied transcriptional activation.
2021-08-05 | PXD024756 | Pride
Project description:Purpose: To study the requirement of Osr1 expression for FAP function during skeletal muscle regeneration. Methods: We sequenced total mRNAs isolated from adult FAPs FACS sorted from 3 and 7 day post injured hindlimb skeletal muscle of Ctrl (Osr1flox/+ CAGG Cre+) and Osr1 cKO (Osr1flox/flox CAGG Cre+) mice. Results: Loss of Osr1 leads to pro-fibrotic orientation of FAPs and impairs both FAP-macrophage and FAP-MuSCs communication network resulting in impaired regenerative myogenesis and persistent fibrosis. Conclusions: Osr1 is a key transcriptional regulator of FAP regenerative function protecting FAPs from assuming a detrimental pro-fibrotic and anti-myogenic state.
2023-03-13 | GSE226683 | GEO
Project description:Fatty infiltration, the ectopic deposition of adipose tissue within skeletal muscle, is mediated via the adipogenic differentiation of fibro-adipogenic progenitors (FAPs). We used single-nuclei and single-cell RNA sequencing to characterize FAP heterogeneity in patients with fatty infiltration. We identified an MME+ FAP subpopulation which, based on ex vivo characterization as well as transplantation experiments, exhibits high adipogenic potential. MME+ FAPs are characterized by low activity of WNT, known to control adipogenic commitment, and are refractory to the inhibitory role of WNT activators. Using preclinical models for muscle damage versus fatty infiltration, we show that many MME+ FAPs undergo apoptosis during muscle regeneration and differentiate into adipocytes under pathological conditions, leading to their depletion. Finally, we utilized the varying fat infiltration levels in human hip muscles to show the depletion of MME+ FAPs in fatty infiltrated human muscle. Altogether, we have identified the dominant adipogenic FAP subpopulation in skeletal muscle.
2023-01-18 | GSE200487 | GEO
Project description:In human dystrophies, the progressive muscle wasting is exacerbated by ectopic deposition of fat and fibrous tissue originating from fibro/adipogenic progenitors (FAPs). In degenerating muscles, the ability of these cells to adjuvate a successful healing is attenuated and FAPs aberrantly expand and differentiate into adipocytes and fibroblasts. Thus, arresting the fibroadipogenic fate of FAPs, without affecting their physiological role, represents a valuable therapeutic strategy for patients affected by muscle diseases. Here, using a panel of adipose progenitor cells including human-derived FAPs coupled with pharmacological perturbations and proteome profiling, we report that LY2090314 interferes with a genuine adipogenic program acting as WNT surrogate for the stabilization of a competent -catenin transcriptional complex. To predict the beneficial impact of LY2090314 in limiting ectopic deposition of fat in human muscles, we combined the Poly-Ethylene-Glycol-Fibrinogen biomimetic matrix with these progenitor cells to create a miniaturized 3D model of adipogenesis. Using this scalable system, we demonstrated that a two-digit nanomolar dose of this compound is effective to repress adipogenesis in a higher 3D scale, thus offering a concrete proof for the use of LY2090314 to limit FAP-derived fat infiltrates in dystrophic muscles.
2023-06-13 | PXD040479 | Pride