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|Title:||Novel basic helix-loop-helix transcription factor hes4 antagonizes the function of twist-1 to regulate lineage commitment of bone marrow stromal/stem cells|
|Citation:||Stem Cells and Development, 2015; 24(11):1297-1308|
|Publisher:||Mary Ann Liebert|
|Dimitrios Cakouros, Sandra Isenmann, Sarah Elizabeth Hemming, Danijela Menicanin, Esther Camp, Andrew Christopher William Zannetinno, and Stan Gronthos|
|Abstract:||Basic helix-loop-helix (bHLH) transcription factors are pivotal regulators of cellular differentiation and development. The bHLH factor, Twist-1 has previously been found to control bone marrow stromal/stem cells (BMSC) self-renewal, life span, and differentiation, however not much is known about its mechanism of action. In this study, we have discovered a novel Twist-1 regulated bHLH gene, Hes4, expressed in humans, but not in mice. Its closest homologue in both humans and mice is Hes1. Overexpression and knockdown studies demonstrated that Hes4 promotes osteogenesis resulting in an increase in Runx2, osteocalcin, osteopontin, and bone sialoprotein expression. Conversely, Hes4 was found to inhibit adipogenesis accompanied by a decrease in PPARγ2, adiponectin, and adipsin expression. In vitro studies indicate that Hes4 employs a mechanism to counteract the negative function of Twist-1 on osteogenesis by binding to Twist-1 and inhibiting the ability of Twist-1 to bind and inhibit Runx2. In vivo chromatin immunoprecipitation and in vitro reporter assays illustrated that Runx2 recruitment to the osterix promoter, was found to be enhanced in the presence of Hes4 and inhibited in the presence of Twist-1. Therefore, Hes4 antagonizes the function of Twist-1 to regulate lineage commitment of BMSC. These studies highlight the potential differences in molecular mechanisms that regulate BMSC osteogenic differentiation between human and mouse|
|Keywords:||Cells, Cultured; Cell Line, Tumor; Osteoblasts; Humans; Complement Factor D; Osteocalcin; Nuclear Proteins; PPAR gamma; Species Specificity; Amino Acid Sequence; Cell Lineage; Molecular Sequence Data; Adipogenesis; Core Binding Factor Alpha 1 Subunit; Basic Helix-Loop-Helix Transcription Factors; Adiponectin; Osteopontin; Mesenchymal Stromal Cells; Twist-Related Protein 1|
|Rights:||©2012 Mary Ann Liebert, Inc.|
|Appears in Collections:||Medical Sciences publications|
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