Novel basic helix-loop-helix transcription factor hes4 antagonizes the function of twist-1 to regulate lineage commitment of bone marrow stromal/stem cells.
Stem Cells Dev
; 24(11): 1297-308, 2015 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-25579220
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.
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Base de dados:
MEDLINE
Assunto principal:
Osteoblastos
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Proteínas Nucleares
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Linhagem da Célula
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Fatores de Transcrição Hélice-Alça-Hélice Básicos
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Proteína 1 Relacionada a Twist
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Células-Tronco Mesenquimais
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article