Epigenetic Control of Osteogenic Lineage Commitment

Montecino, Martín; Carrasco, Margarita E.; Nardocci, Gino

doi:10.3389/fcell.2020.611197

Cited by 20 publications

(19 citation statements)

References 105 publications

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“…Another remarkable group of enriched pathways belonged to metabolism, which includes genes belonging to glycolysis/glyconeogenesis , biosynthesis of amino acids and carbon metabolism pathways . Finally, an infection-mediated deregulation of genes belonging to the estrogen signaling pathway and the osteoblast differentiation pathway was noteworthy ( Kovats, 2015 ; Montecino et al., 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…The amplitude of the expression could, however, be also related to the deregulation of genes involved in chromatin remodeling. Beside immunity, infection-mediated deregulation of genes belonging to the estrogen signaling and osteoblast differentiation pathways could also be due to chromatin-based regulation ( Kovats, 2015 ; Montecino et al., 2021 ). The expression of cellular genes is indeed dependent on the state of chromatin compaction, governed by histone modification and DNA methylation profiles, also referred to as “epigenetic regulation”.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome Architecture of Osteoblastic Cells Infected With Staphylococcus aureus Reveals Strong Inflammatory Responses and Signatures of Metabolic and Epigenetic Dysregulation

Nicolas

Deplanche

Commère

et al. 2022

Front. Cell. Infect. Microbiol.

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Staphylococcus aureus is an opportunistic pathogen that causes a range of devastating diseases including chronic osteomyelitis, which partially relies on the internalization and persistence of S. aureus in osteoblasts. The identification of the mechanisms of the osteoblast response to intracellular S. aureus is thus crucial to improve the knowledge of this infectious pathology. Since the signal from specifically infected bacteria-bearing cells is diluted and the results are confounded by bystander effects of uninfected cells, we developed a novel model of long-term infection. Using a flow cytometric approach we isolated only S. aureus-bearing cells from mixed populations that allows to identify signals specific to intracellular infection. Here we present an in-depth analysis of the effect of long-term S. aureus infection on the transcriptional program of human osteoblast-like cells. After RNA-seq and KEGG and Reactome pathway enrichment analysis, the remodeled transcriptomic profile of infected cells revealed exacerbated immune and inflammatory responses, as well as metabolic dysregulations that likely influence the intracellular life of bacteria. Numerous genes encoding epigenetic regulators were downregulated. The later included genes coding for components of chromatin-repressive complexes (e.g., NuRD, BAHD1 and PRC1) and epifactors involved in DNA methylation. Sets of genes encoding proteins of cell adhesion or neurotransmission were also deregulated. Our results suggest that intracellular S. aureus infection has a long-term impact on the genome and epigenome of host cells, which may exert patho-physiological dysfunctions additionally to the defense response during the infection process. Overall, these results not only improve our conceptual understanding of biological processes involved in the long-term S. aureus infections of osteoblast-like cells, but also provide an atlas of deregulated host genes and biological pathways and identify novel markers and potential candidates for prophylactic and therapeutic approaches.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcriptome Architecture of Osteoblastic Cells Infected With Staphylococcus aureus Reveals Strong Inflammatory Responses and Signatures of Metabolic and Epigenetic Dysregulation

Nicolas

Deplanche

Commère

et al. 2022

Front. Cell. Infect. Microbiol.

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show abstract

Section: Introductionmentioning

confidence: 99%

“…Osteogenesis is mediated by the dynamic activation and suppression of gene expression programs in osteoblasts that produce a collagenous mineralized matrix 1 – 9 . The production and deposition of bone-specific extracellular matrix proteins is controlled by epigenetic mechanisms that modulate the accessibility of transcription factors to gene loci in chromatin 1 , 10 . Genetic studies have established that many distinct epigenetic regulators contribute to skeletal development and bone formation in vivo, including enzymes and proteins that control DNA methylation, as well as histone acetylation and methylation 10 – 12 .…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-101a enhances trabecular bone accrual in male mice

Dudakovic

Jerez

Deosthale

et al. 2022

Sci Rep

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High-throughput microRNA sequencing was performed during differentiation of MC3T3-E1 osteoblasts to develop working hypotheses for specific microRNAs that control osteogenesis. The expression data show that miR-101a, which targets the mRNAs for the epigenetic enzyme Ezh2 and many other proteins, is highly upregulated during osteoblast differentiation and robustly expressed in mouse calvaria. Transient elevation of miR-101a suppresses Ezh2 levels, reduces tri-methylation of lysine 27 in histone 3 (H3K27me3; a heterochromatic mark catalyzed by Ezh2), and accelerates mineralization of MC3T3-E1 osteoblasts. We also examined skeletal phenotypes of an inducible miR-101a transgene under direct control of doxycycline administration. Experimental controls and mir-101a over-expressing mice were exposed to doxycycline in utero and postnatally (up to 8 weeks of age) to maximize penetrance of skeletal phenotypes. Male mice that over-express miR-101a have increased total body weight and longer femora. MicroCT analysis indicate that these mice have increased trabecular bone volume fraction, trabecular number and trabecular thickness with reduced trabecular spacing as compared to controls. Histomorphometric analysis demonstrates a significant reduction in osteoid volume to bone volume and osteoid surface to bone surface. Remarkably, while female mice also exhibit a significant increase in bone length, no significant changes were noted by microCT (trabecular bone parameters) and histomorphometry (osteoid parameters). Hence, miR-101a upregulation during osteoblast maturation and the concomitant reduction in Ezh2 mediated H3K27me3 levels may contribute to the enhanced trabecular bone parameters in male mice. However, the sex-specific effect of miR-101a indicates that more intricate epigenetic mechanisms mediate physiological control of bone formation and homeostasis.

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“…Special attention is dedicated to mechanisms of epigenetic control operating at the SMAD family member 3 (SMAD3) and Sp7 transcription factor (Sp7) coding for the two principal master regulators of the osteogenic lineage during mesenchymal stem cell commitment. For example, SMAD3 has been shown to bind to the osteopontin promoter as a sequence specific activator [16,17].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Osteoinductivity Assay of Hydroxylapatite Scaffolds, Obtained with Biomorphic Transformation Processes, Assessed Using Human Adipose Stem Cell Cultures

Iaquinta

Torreggiani

Mazziotta

et al. 2021

IJMS

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In this study, the in vitro biocompatibility and osteoinductive ability of a recently developed biomorphic hydroxylapatite ceramic scaffold (B-HA) derived from transformation of wood structures were analyzed using human adipose stem cells (hASCs). Cell viability and metabolic activity were evaluated in hASCs, parental cells and in recombinant genetically engineered hASC-eGFP cells expressing the green fluorescence protein. B-HA osteoinductivity properties, such as differentially expressed genes (DEG) involved in the skeletal development pathway, osteocalcin (OCN) protein expression and mineral matrix deposition in hASCs, were evaluated. In vitro induction of osteoblastic genes, such as Alkaline phosphatase (ALPL), Bone gamma-carboxyglutamate (gla) protein (BGLAP), SMAD family member 3 (SMAD3), Sp7 transcription factor (SP7) and Transforming growth factor, beta 3 (TGFB3) and Tumor necrosis factor (ligand) superfamily, member 11 (TNFSF11)/Receptor activator of NF-κB (RANK) ligand (RANKL), involved in osteoclast differentiation, was undertaken in cells grown on B-HA. Chondrogenic transcription factor SRY (sex determining region Y)-box 9 (SOX9), tested up-regulated in hASCs grown on the B-HA scaffold. Gene expression enhancement in the skeletal development pathway was detected in hASCs using B-HA compared to sintered hydroxylapatite (S-HA). OCN protein expression and calcium deposition were increased in hASCs grown on B-HA in comparison with the control. This study demonstrates the biocompatibility of the novel biomorphic B-HA scaffold and its potential use in osteogenic differentiation for hASCs. Our data highlight the relevance of B-HA for bone regeneration purposes.

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Epigenetic Control of Osteogenic Lineage Commitment

Cited by 20 publications

References 105 publications

Transcriptome Architecture of Osteoblastic Cells Infected With Staphylococcus aureus Reveals Strong Inflammatory Responses and Signatures of Metabolic and Epigenetic Dysregulation

Transcriptome Architecture of Osteoblastic Cells Infected With Staphylococcus aureus Reveals Strong Inflammatory Responses and Signatures of Metabolic and Epigenetic Dysregulation

MicroRNA-101a enhances trabecular bone accrual in male mice

In Vitro Osteoinductivity Assay of Hydroxylapatite Scaffolds, Obtained with Biomorphic Transformation Processes, Assessed Using Human Adipose Stem Cell Cultures

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