Open AccessEpigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells
Author(s) -
Ali Dalia,
Hamam Rimi,
Alfayez Musaed,
Kassem Moustapha,
Aldahmash Abdullah,
Alajez Nehad M.
Publication year - 2016
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.5966/sctm.2015-0331
Subject(s) - epigenetics , biology , cellular differentiation , mesenchymal stem cell , epigenetic regulation of neurogenesis , microbiology and biotechnology , histone deacetylase , chromatin immunoprecipitation , stem cell , wnt signaling pathway , dna methylation , cancer research , histone , signal transduction , chromatin remodeling , genetics , promoter , gene expression , gene
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.