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Novel basic helix-loop-helix transcription factor hes4 antagonizes the function of twist-1 to regulate lineage commitment of bone marrow stromal/stem cells

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dc.contributor.authorCakouros, D.
dc.contributor.authorIsenmann, S.
dc.contributor.authorHemming, S.
dc.contributor.authorMenicanin, D.
dc.contributor.authorCamp, E.
dc.contributor.authorZannetinno, A.
dc.contributor.authorGronthos, S.
dc.date.issued2015
dc.description.abstractBasic 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
dc.description.statementofresponsibilityDimitrios Cakouros, Sandra Isenmann, Sarah Elizabeth Hemming, Danijela Menicanin, Esther Camp, Andrew Christopher William Zannetinno, and Stan Gronthos
dc.identifier.citationStem Cells and Development, 2015; 24(11):1297-1308
dc.identifier.doi10.1089/scd.2014.0471
dc.identifier.issn1557-8534
dc.identifier.issn1557-8534
dc.identifier.orcidCakouros, D. [0000-0001-6136-0761]
dc.identifier.orcidMenicanin, D. [0000-0002-1178-2293]
dc.identifier.orcidGronthos, S. [0000-0002-6225-3084]
dc.identifier.urihttp://hdl.handle.net/2440/92090
dc.language.isoen
dc.publisherMary Ann Liebert
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1046053
dc.rights©2012 Mary Ann Liebert, Inc.
dc.source.urihttps://doi.org/10.1089/scd.2014.0471
dc.subjectCells, Cultured
dc.subjectCell Line, Tumor
dc.subjectOsteoblasts
dc.subjectMesenchymal Stem Cells
dc.subjectHumans
dc.subjectComplement Factor D
dc.subjectOsteocalcin
dc.subjectNuclear Proteins
dc.subjectPPAR gamma
dc.subjectSpecies Specificity
dc.subjectAmino Acid Sequence
dc.subjectCell Lineage
dc.subjectMolecular Sequence Data
dc.subjectAdipogenesis
dc.subjectCore Binding Factor Alpha 1 Subunit
dc.subjectBasic Helix-Loop-Helix Transcription Factors
dc.subjectAdiponectin
dc.subjectOsteopontin
dc.subjectTwist-Related Protein 1
dc.titleNovel basic helix-loop-helix transcription factor hes4 antagonizes the function of twist-1 to regulate lineage commitment of bone marrow stromal/stem cells
dc.typeJournal article
pubs.publication-statusPublished

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