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MicroRNA Network Regulation of Developmental Bone Toxicity in a Human Embryonic Stem Cell Osteogenic Model

ABSTRACT: Developmental exposure to environmental toxicants is a cause of skeletal abnormalities. Yet the molecular mechanisms linking early exposure to impaired bone formation remain undefined. Skeletal tissues arise from both neural crest- and mesoderm-derived lineages that rely on shared osteogenic differentiation programs, suggesting that disruption of common regulatory processes may contribute to diverse skeletal outcomes. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene networks and have appeared as indicators of toxicant-induced perturbation. In this study, we examined whether developmentally relevant toxicants are associated with miRNA regulatory networks during osteogenic differentiation. Using a human embryonic stem cell (hESC)-based osteogenic differentiation model, we assessed the effects of nine toxicants spanning distinct primary mechanisms. Toxicant exposure impaired osteogenic differentiation at their IC50, as reflected by altered expression of osteogenic markers and transcriptional remodeling. Global miRNA profiling revealed dysregulation of miRNAs enriched for bone-related biological processes, including regulators of osteogenic commitment and differentiation timing. Integrated miRNA–mRNA network analysis identified a subset of miRNAs linked to core osteogenic and lineage-associated pathways, including RUNX2-dependent transcription and BMP and Wnt signaling. Modulation of representative miRNAs produced osteogenic outcomes consistent with those observed following toxicant exposure and, in some cases, was associated with partial restoration of differentiation in exposed cultures. Collectively, these findings indicate that chemically diverse developmental toxicants are associated with miRNA-mediated regulatory patterns during osteogenic differentiation. Identification of conserved miRNA signatures provides mechanistic insight into developmental bone toxicity and supports the use of miRNA network analysis as a human-relevant endpoint for skeletal hazard identification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324490 | GEO | 2026/05/31

REPOSITORIES: GEO

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Project description:Developmental exposure to environmental toxicants is a cause of skeletal abnormalities. Yet the molecular mechanisms linking early exposure to impaired bone formation remain undefined. Skeletal tissues arise from both neural crest- and mesoderm-derived lineages that rely on shared osteogenic differentiation programs, suggesting that disruption of common regulatory processes may contribute to diverse skeletal outcomes. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene networks and have appeared as indicators of toxicant-induced perturbation. In this study, we examined whether developmentally relevant toxicants are associated with miRNA regulatory networks during osteogenic differentiation. Using a human embryonic stem cell (hESC)-based osteogenic differentiation model, we assessed the effects of nine toxicants spanning distinct primary mechanisms. Toxicant exposure impaired osteogenic differentiation at their IC50, as reflected by altered expression of osteogenic markers and transcriptional remodeling. Global miRNA profiling revealed dysregulation of miRNAs enriched for bone-related biological processes, including regulators of osteogenic commitment and differentiation timing. Integrated miRNA–mRNA network analysis identified a subset of miRNAs linked to core osteogenic and lineage-associated pathways, including RUNX2-dependent transcription and BMP and Wnt signaling. Modulation of representative miRNAs produced osteogenic outcomes consistent with those observed following toxicant exposure and, in some cases, was associated with partial restoration of differentiation in exposed cultures. Collectively, these findings indicate that chemically diverse developmental toxicants are associated with miRNA-mediated regulatory patterns during osteogenic differentiation. Identification of conserved miRNA signatures provides mechanistic insight into developmental bone toxicity and supports the use of miRNA network analysis as a human-relevant endpoint for skeletal hazard identification.

Project description:Proctor2017 - Identifying microRNA for muscle regeneration during ageing (Mirs_in_muscle) This model is described in the article: Using computer simulation models to investigate the most promising microRNAs to improve muscle regeneration during ageing Carole J. Proctor & Katarzyna Goljanek-Whysall Nature Scientific Reports Abstract: MicroRNAs (miRNAs) regulate gene expression through interactions with target sites within mRNAs, leading to enhanced degradation of the mRNA or inhibition of translation. Skeletal muscle expresses many different miRNAs with important roles in adulthood myogenesis (regeneration) and myofibre hypertrophy and atrophy, processes associated with muscle ageing. However, the large number of miRNAs and their targets mean that a complex network of pathways exists, making it difficult to predict the effect of selected miRNAs on age-related muscle wasting. Computational modelling has the potential to aid this process as it is possible to combine models of individual miRNA:target interactions to form an integrated network. As yet, no models of these interactions in muscle exist. We created the first model of miRNA:target interactions in myogenesis based on experimental evidence of individual miRNAs which were next validated and used to make testable predictions. Our model confirms that miRNAs regulate key interactions during myogenesis and can act by promoting the switch between quiescent/proliferating/differentiating myoblasts and by maintaining the differentiation process. We propose that a threshold level of miR-1 acts in the initial switch to differentiation, with miR-181 keeping the switch on and miR-378 maintaining the differentiation and miR-143 inhibiting myogenesis. This model is hosted on BioModels Database and identified by: MODEL1704110004. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Proctor2017 - Identifying microRNA for muscle regeneration during ageing (Mir1_in_muscle) This model is described in the article: Using computer simulation models to investigate the most promising microRNAs to improve muscle regeneration during ageing Carole J. Proctor & Katarzyna Goljanek-Whysall Nature Scientific Reports Abstract: MicroRNAs (miRNAs) regulate gene expression through interactions with target sites within mRNAs, leading to enhanced degradation of the mRNA or inhibition of translation. Skeletal muscle expresses many different miRNAs with important roles in adulthood myogenesis (regeneration) and myofibre hypertrophy and atrophy, processes associated with muscle ageing. However, the large number of miRNAs and their targets mean that a complex network of pathways exists, making it difficult to predict the effect of selected miRNAs on age-related muscle wasting. Computational modelling has the potential to aid this process as it is possible to combine models of individual miRNA:target interactions to form an integrated network. As yet, no models of these interactions in muscle exist. We created the first model of miRNA:target interactions in myogenesis based on experimental evidence of individual miRNAs which were next validated and used to make testable predictions. Our model confirms that miRNAs regulate key interactions during myogenesis and can act by promoting the switch between quiescent/proliferating/differentiating myoblasts and by maintaining the differentiation process. We propose that a threshold level of miR-1 acts in the initial switch to differentiation, with miR-181 keeping the switch on and miR-378 maintaining the differentiation and miR-143 inhibiting myogenesis. This model is hosted on BioModels Database and identified by: MODEL1704110000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Proctor2017 - Identifying microRNA for muscle regeneration during ageing (Mir143_in_muscle) This model is described in the article: Using computer simulation models to investigate the most promising microRNAs to improve muscle regeneration during ageing Carole J. Proctor & Katarzyna Goljanek-Whysall Scientific Reports Abstract: MicroRNAs (miRNAs) regulate gene expression through interactions with target sites within mRNAs, leading to enhanced degradation of the mRNA or inhibition of translation. Skeletal muscle expresses many different miRNAs with important roles in adulthood myogenesis (regeneration) and myofibre hypertrophy and atrophy, processes associated with muscle ageing. However, the large number of miRNAs and their targets mean that a complex network of pathways exists, making it difficult to predict the effect of selected miRNAs on age-related muscle wasting. Computational modelling has the potential to aid this process as it is possible to combine models of individual miRNA:target interactions to form an integrated network. As yet, no models of these interactions in muscle exist. We created the first model of miRNA:target interactions in myogenesis based on experimental evidence of individual miRNAs which were next validated and used to make testable predictions. Our model confirms that miRNAs regulate key interactions during myogenesis and can act by promoting the switch between quiescent/proliferating/differentiating myoblasts and by maintaining the differentiation process. We propose that a threshold level of miR-1 acts in the initial switch to differentiation, with miR-181 keeping the switch on and miR-378 maintaining the differentiation and miR-143 inhibiting myogenesis. This model is hosted on BioModels Database and identified by: MODEL1704110003. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Proctor2017 - Identifying microRNA for muscle regeneration during ageing (Mir181_in_muscle) This model is described in the article: Using computer simulation models to investigate the most promising microRNAs to improve muscle regeneration during ageing Carole J. Proctor & Katarzyna Goljanek-Whysall Scientific Reports Abstract: MicroRNAs (miRNAs) regulate gene expression through interactions with target sites within mRNAs, leading to enhanced degradation of the mRNA or inhibition of translation. Skeletal muscle expresses many different miRNAs with important roles in adulthood myogenesis (regeneration) and myofibre hypertrophy and atrophy, processes associated with muscle ageing. However, the large number of miRNAs and their targets mean that a complex network of pathways exists, making it difficult to predict the effect of selected miRNAs on age-related muscle wasting. Computational modelling has the potential to aid this process as it is possible to combine models of individual miRNA:target interactions to form an integrated network. As yet, no models of these interactions in muscle exist. We created the first model of miRNA:target interactions in myogenesis based on experimental evidence of individual miRNAs which were next validated and used to make testable predictions. Our model confirms that miRNAs regulate key interactions during myogenesis and can act by promoting the switch between quiescent/proliferating/differentiating myoblasts and by maintaining the differentiation process. We propose that a threshold level of miR-1 acts in the initial switch to differentiation, with miR-181 keeping the switch on and miR-378 maintaining the differentiation and miR-143 inhibiting myogenesis. This model is hosted on BioModels Database and identified by: MODEL1704110001. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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MicroRNA Network Regulation of Developmental Bone Toxicity in a Human Embryonic Stem Cell Osteogenic Model

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