Project description:Studying chemical disturbances during neural differentiation of mES cells has been established as an alternative in vitro testing approach for the identification of developmental toxicants. miRNAs represent a class of small regulatory RNA molecules, which bind to target mRNAs thereby repressing their translation. Many studies have shown an essential role of miRNAs in regulation of gene expression during development and ESC differentiation. Thus, neural differentiation of ESC in vitro allows investigating the role of miRNAs in chemical-mediated developmental toxicity. We analyzed the expression of miRNAs and transcriptomics changes during neural differentiation of mESC exposed to the developmental neurotoxicant sodium valproate (VPA). A total of 110 miRNAs and 377 mRNAs were identified differently expressed in neural differentiating mES cells under VPA treatment (300ÂµM) compared to solvent control on day 16 of differentiation. Analysis of miRNA expression revealed that valproate switches the lineage specification from neural to myogenic differentiation (upregulation of muscle-enriched miRNAs mir-206, mir-133a and mir-10a and downregulation of neuro-specific miRNAs mir-124a, mir-128 and mir-137). The findings on the miRNA level could be confirmed on mRNA level (induction of expression of myogenic regulatory factors (MRFs) as well as muscle specific genes (Actc1, calponin, myosin light chain, asporin, decorin) and repression of genes involved in neurogenesis (Otx1 and 2, Zic3, 4, 5)) as well as morphologically by immunocytochemistry. The observed results were VPA specific and most probably due to inhibition of histone deacetylase (HDAC) activity of VPA for two reasons: (i) we did not observe any induction of muscle specific miRNAs in neural differentiating ES cells exposed to the unrelated developmental neurotoxicant sodium arsenite; (ii) expression of muscle specific mir-206 and muscle enriched mir-10a was similarly increased in cells exposed to a structurally different HDAC inhibitor, trichostatin A (TSA). Furthermore, using our in vitro cell system we could confirm an aberrant expression of known VPA target genes and genes involved in neural tube closure. We conclude that miRNA expression profiling is a suitable molecular endpoint for developmental neurotoxicity. Observed lineage shift into myogenesis, where miRNAs play a significant role, could be a major developmental neurotoxical mechanism of VPA. We used microarray approach to identify altered miRNA expression in neural differentiated mES cells exposed to two known developmental neurotxicants and epigenetic active substances, sodium valproate (VPA) and sodium arsenite (As) mES cells line W4 were induced to differnetiate to neurons under exposure to VPA and As for 16 days. RNA for microarrays was collected on day 16 of differentiation from three biological replicates of solvent controls (PBS was used as a solvent for VPA and H20 for As) or substance treated cells.

Project description:Studying chemical disturbances during neural differentiation of mES cells has been established as an alternative in vitro testing approach for the identification of developmental toxicants. miRNAs represent a class of small regulatory RNA molecules, which bind to target mRNAs thereby repressing their translation. Many studies have shown an essential role of miRNAs in regulation of gene expression during development and ESC differentiation. Thus, neural differentiation of ESC in vitro allows investigating the role of miRNAs in chemical-mediated developmental toxicity. We analyzed the expression of miRNAs and transcriptomics changes during neural differentiation of mESC exposed to the developmental neurotoxicant sodium valproate (VPA). A total of 110 miRNAs and 377 mRNAs were identified differently expressed in neural differentiating mES cells under VPA treatment (300µM) compared to solvent control on day 16 of differentiation. Analysis of miRNA expression revealed that valproate switches the lineage specification from neural to myogenic differentiation (upregulation of muscle-enriched miRNAs mir-206, mir-133a and mir-10a and downregulation of neuro-specific miRNAs mir-124a, mir-128 and mir-137). The findings on the miRNA level could be confirmed on mRNA level (induction of expression of myogenic regulatory factors (MRFs) as well as muscle specific genes (Actc1, calponin, myosin light chain, asporin, decorin) and repression of genes involved in neurogenesis (Otx1 and 2, Zic3, 4, 5)) as well as morphologically by immunocytochemistry. The observed results were VPA specific and most probably due to inhibition of histone deacetylase (HDAC) activity of VPA for two reasons: (i) we did not observe any induction of muscle specific miRNAs in neural differentiating ES cells exposed to the unrelated developmental neurotoxicant sodium arsenite; (ii) expression of muscle specific mir-206 and muscle enriched mir-10a was similarly increased in cells exposed to a structurally different HDAC inhibitor, trichostatin A (TSA). Furthermore, using our in vitro cell system we could confirm an aberrant expression of known VPA target genes and genes involved in neural tube closure. We conclude that miRNA expression profiling is a suitable molecular endpoint for developmental neurotoxicity. Observed lineage shift into myogenesis, where miRNAs play a significant role, could be a major developmental neurotoxical mechanism of VPA. We used microarray approach to identify altered miRNA expression in neural differentiated mES cells exposed to two known developmental neurotxicants and epigenetic active substances, sodium valproate (VPA) and sodium arsenite (As)

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 (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.

Project description:Proctor2017 - Identifying microRNA for muscle regeneration during ageing (Mir378_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: MODEL1704110002. 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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Transcriptomics changes in neural differentiated mouse embryonic stem cells (mESCs) under exposure to sodium valproate

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