Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells

Autor: Nehad M. Alajez, Musaed Alfayez, Moustapha Kassem, Rimi Hamam, Dalia Ali, Abdullah Aldahmash
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Epigenetic regulation of neurogenesis
Hydroxamic Acids
Epigenesis
Genetic
Myoblasts
Skeletal/drug effects
0302 clinical medicine
Adipogenesis/drug effects
Osteogenesis
Histone deacetylase inhibitors
Signal Transduction/drug effects
Adipocytes
Oligonucleotide Array Sequence Analysis
lcsh:R5-920
Adipocyte
Adipogenesis
lcsh:Cytology
Osteoblast
Wnt signaling pathway
Epigenetic
Gene Expression Regulation
Developmental
Cell Differentiation
General Medicine
Benzofurans/pharmacology
Cell biology
Osteogenesis/drug effects
Mesenchymal Stem Cells/drug effects
Phenotype
030220 oncology & carcinogenesis
Stem cell
lcsh:Medicine (General)
Signal Transduction
Chromatin Immunoprecipitation
Genotype
Myoblasts
Skeletal
Transcription Factors/genetics
Biology
Epigenesis
Genetic/drug effects
Cell Line
03 medical and health sciences
Osteoblasts/drug effects
Humans
Cell Lineage
Epigenetics
lcsh:QH573-671
Transcription factor
Benzofurans
Gene Library
Osteoblasts
Gene Expression Profiling
Mesenchymal stem cell
Computational Biology
Mesenchymal Stem Cells
Cell Biology
Cell-Based Drug Development
Screening
and Toxicology
equipment and supplies
Molecular biology
Histone Deacetylase Inhibitors
030104 developmental biology
Cell Differentiation/drug effects
Mesenchymal stem cells
Histone deacetylase
Gene Expression Profiling/methods
Chromatin immunoprecipitation
Histone Deacetylase Inhibitors/pharmacology
Developmental Biology
Adipocytes/drug effects
Hydroxamic Acids/pharmacology
Transcription Factors
Zdroj: 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
Stem Cells Translational Medicine, Vol 5, Iss 8, Pp 1036-1047 (2016)
DOI: 10.5966/sctm.2015-0331
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.
Databáze: OpenAIRE
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