Abstract
SH3BP2 activating mutations lead to an unique clinical condition in which patients develop symmetrical bone resorptive lesions of the jaw, a condition termed cherubism. Due to this specific temporal sequence and location of bone resorption, we investigated the transcriptional regulation of SH3BP2 expression. Analyses of 5′- and 3′-serial promoter deletions defined the core promoter/regulatory elements, including two repressor sites (from −1,200 to −1,000 and from +86 to +115, respectively) and two activator sites (a PARP1 binding site from −44 to −21 and a second activator site from +57 to +86). We identified that PARP1 binds to DNA from −44 to −21 by Streptavidin–biotin purification and confirmed this binding by electrophoretic mobility shift assay (EMSA). Mutagenesis of the PARP1 binding site on the SH3BP2 promoter showed that this binding site is essential for SH3BP2 expression. EMSA and chromatin immunoprecipitation (ChIP) assays confirmed that PARP1 was able to bind to the SH3BP2 promoter in vitro and in vivo. Indeed, knockout of Parp1 in mice BMMs reduced expression of SH3BP2. These results demonstrate that PARP1 regulates expression of SH3BP2.
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