Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells
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| Názov: | Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells |
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| Autori: | Rimi Hamam, Abdullah Aldahmash, Musaed Alfayez, Nehad M. Alajez, Dalia Ali, Moustapha Kassem |
| Zdroj: | Stem Cells Translational Medicine, Vol 5, Iss 8, Pp 1036-1047 (2016) Ali, D, Hamam, R, Alfayez, M, Kassem, M, Aldahmash, A & Alajez, N M 2016, ' Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells ', Stem Cells Translational Medicine, vol. 5, no. 8, pp. 1036-1047 . https://doi.org/10.5966/sctm.2015-0331 |
| Informácie o vydavateľovi: | Oxford University Press (OUP), 2016. |
| Rok vydania: | 2016 |
| Predmety: | 0301 basic medicine, Medicine (General), Hydroxamic Acids, Epigenesis, Genetic, Myoblasts, Myoblasts, Skeletal/drug effects, Adipogenesis/drug effects, Signal Transduction/drug effects, Histone deacetylase inhibitors, Adipocytes, Developmental, Oligonucleotide Array Sequence Analysis, Adipocyte, Adipogenesis, Osteoblast, Epigenetic, Gene Expression Regulation, Developmental, Cell Differentiation, Benzofurans/pharmacology, Osteogenesis/drug effects, Mesenchymal Stem Cells/drug effects, Phenotype, Chromatin Immunoprecipitation, Genotype, Myoblasts, Skeletal, Transcription Factors/genetics, Epigenesis, Genetic/drug effects, Cell Line, Osteoblasts/drug effects, 03 medical and health sciences, R5-920, Humans, Cell Lineage, Skeletal/drug effects, Benzofurans, Gene Library, Genetic/drug effects, Osteoblasts, QH573-671, Gene Expression Profiling, Computational Biology, Mesenchymal Stem Cells, Histone Deacetylase Inhibitors, Gene Expression Regulation, Cell Differentiation/drug effects, Mesenchymal stem cells, Gene Expression Profiling/methods, Cytology, Histone Deacetylase Inhibitors/pharmacology, Epigenesis, Adipocytes/drug effects, Hydroxamic Acids/pharmacology |
| Popis: | The epigenetic mechanisms promoting lineage-specific commitment of human skeletal (mesenchymal or stromal) stem cells (hMSCs) into adipocytes or osteoblasts are still not fully understood. Herein, we performed an epigenetic library functional screen and identified several novel compounds, including abexinostat, which promoted adipocytic and osteoblastic differentiation of hMSCs. Using gene expression microarrays, chromatin immunoprecipitation for H3K9Ac combined with high-throughput DNA sequencing (ChIP-seq), and bioinformatics, we identified several key genes involved in regulating stem cell proliferation and differentiation that were targeted by abexinostat. Concordantly, ChIP-quantitative polymerase chain reaction revealed marked increase in H3K9Ac epigenetic mark on the promoter region of AdipoQ, FABP4, PPARγ, KLF15, CEBPA, SP7, and ALPL in abexinostat-treated hMSCs. Pharmacological inhibition of focal adhesion kinase (PF-573228) or insulin-like growth factor-1R/insulin receptor (NVP-AEW51) signaling exhibited significant inhibition of abexinostat-mediated adipocytic differentiation, whereas inhibition of WNT (XAV939) or transforming growth factor-β (SB505124) signaling abrogated abexinostat-mediated osteogenic differentiation of hMSCs. Our findings provide insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways governing adipocyte and osteoblast differentiation. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies and tissue engineering. Significance This unbiased epigenetic library functional screen identified several novel compounds, including abexinostat, that promoted adipocytic and osteoblastic differentiation of human skeletal (mesenchymal or stromal) stem cells (hMSCs). These data provide new insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways controlling adipocyte and osteoblast differentiation of hMSCs. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies for tissue engineering, bone disease, obesity, and metabolic-disorders. |
| Druh dokumentu: | Article |
| Popis súboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 2157-6580 2157-6564 |
| DOI: | 10.5966/sctm.2015-0331 |
| Prístupová URL adresa: | https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdfdirect/10.5966/sctm.2015-0331 https://pubmed.ncbi.nlm.nih.gov/27194745 https://doaj.org/article/eebe0aeffba64f40b9efaa48b710bc81 https://www.ncbi.nlm.nih.gov/pubmed/27194745 https://core.ac.uk/display/50718679 http://findresearcher.sdu.dk/portal/da/publications/epigenetic-library-screen-identifies-abexinostat-as-novel-regulator-of-adipocytic-and-osteoblastic-differentiation-of-human-skeletal-mesenchymal-stem-cells(56d038ea-347b-40c2-bfb6-2cd3116da8c5).html https://onlinelibrary.wiley.com/doi/10.5966/sctm.2015-0331/full https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.5966/sctm.2015-0331 https://pubmed.ncbi.nlm.nih.gov/27194745/ https://findresearcher.sdu.dk:8443/ws/files/134252860/Epigenetic_Library_Screen_Identifies_Abexinostat_as_Novel_Regulator_of_Adipocytic_and_Osteoblastic_Differentiation_of_Human_Skeletal_Mesenchymal_Stem_Cells.pdf https://portal.findresearcher.sdu.dk/da/publications/56d038ea-347b-40c2-bfb6-2cd3116da8c5 https://doi.org/10.5966/sctm.2015-0331 |
| Rights: | OUP Standard Publication Reuse CC BY NC |
| Prístupové číslo: | edsair.doi.dedup.....77a0470d79cc6be8aed62e38f8746b4a |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | The epigenetic mechanisms promoting lineage-specific commitment of human skeletal (mesenchymal or stromal) stem cells (hMSCs) into adipocytes or osteoblasts are still not fully understood. Herein, we performed an epigenetic library functional screen and identified several novel compounds, including abexinostat, which promoted adipocytic and osteoblastic differentiation of hMSCs. Using gene expression microarrays, chromatin immunoprecipitation for H3K9Ac combined with high-throughput DNA sequencing (ChIP-seq), and bioinformatics, we identified several key genes involved in regulating stem cell proliferation and differentiation that were targeted by abexinostat. Concordantly, ChIP-quantitative polymerase chain reaction revealed marked increase in H3K9Ac epigenetic mark on the promoter region of AdipoQ, FABP4, PPARγ, KLF15, CEBPA, SP7, and ALPL in abexinostat-treated hMSCs. Pharmacological inhibition of focal adhesion kinase (PF-573228) or insulin-like growth factor-1R/insulin receptor (NVP-AEW51) signaling exhibited significant inhibition of abexinostat-mediated adipocytic differentiation, whereas inhibition of WNT (XAV939) or transforming growth factor-β (SB505124) signaling abrogated abexinostat-mediated osteogenic differentiation of hMSCs. Our findings provide insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways governing adipocyte and osteoblast differentiation. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies and tissue engineering. Significance This unbiased epigenetic library functional screen identified several novel compounds, including abexinostat, that promoted adipocytic and osteoblastic differentiation of human skeletal (mesenchymal or stromal) stem cells (hMSCs). These data provide new insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways controlling adipocyte and osteoblast differentiation of hMSCs. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies for tissue engineering, bone disease, obesity, and metabolic-disorders. |
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| ISSN: | 21576580 21576564 |
| DOI: | 10.5966/sctm.2015-0331 |