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  • Title: Nuclear matrix-targeting of the osteogenic factor Runx2 is essential for its recognition and activation of the alkaline phosphatase gene.
    Author: Weng JJ, Su Y.
    Journal: Biochim Biophys Acta; 2013 Mar; 1830(3):2839-52. PubMed ID: 23287548.
    Abstract:
    BACKGROUND: A good understanding of the mechanism of gene regulation that is involved in bone mineralization is critical for the design of anabolic treatments for bone deficiency diseases. Alkaline phosphatase (ALP) expressed by osteoblasts plays an important role in promoting bone mineralization by hydrolyzing pyrophosphate. However, the mechanism by which the expression of ALP is regulated during osteoblast differentiation has not been thoroughly investigated. METHODS: Chromatin immunoprecipitation. EMSA and mutagenesis were used to identify the Runx2 binding sites on ALP gene and to analyze the role of nuclear matrix-localization of Runx2 on the recognition and activation of ALP gene. RESULTS: Using chromatin immunoprecipitation, we determined that both ectopic and endogenous Runx2 bound to ALP intron 1 in a region containing a cluster of five putative core-sites. The third one (11C3) among those fives was bound most strongly in vitro by Runx2 and acted as a Runx2-dependent transcriptional enhancer. Furthermore, a Runx2 mutant lacking the nuclear matrix-targeting sequence (Runx2deltaNMTS) bound to the ALP gene less efficiently than the wild-type protein and a Runx2 mutant that is deficient in its ability to bind to DNA (Runx2K120A) accumulated largely in the nuclear matrix. CONCLUSIONS: Nuclear matrix-localization of Runx2 influences its ALP gene recognition. GENERAL SIGNIFICANCE: Our results showed for the first time that ALP is a direct target gene of Runx2 and illustrated that the recognition/binding and activation of the ALP by this transcription factor are dependent on its nuclear matrix-targeting.
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