Competing Repressive Factors Control Bone Morphogenetic Protein 2 (BMP2) in Mesenchymal Cells

The amount, timing, and location of bone morphogenetic protein 2 (BMP2) synthesis influences the differentiation of pluripotent mesenchymal cells in embryos and adults. The BMP2 3'untranslated region (3'UTR) contains a highly conserved AU-rich element (ARE) embedded in a sequence that commonly represses gene expression in mesenchymal cells. Computational analyses indicate that this site also may bind several microRNAs (miRNAs). Although miRNAs frequently target AU-rich regions, this ARE is unusual because the miRNAs directly span the ARE. We began to characterize the factors that may regulate Bmp2 expression via this complex site. The activating protein HuR (Hu antigen R, ELAVL1, HGNC:3312) directly binds this ARE and can activate gene expression. An miRNA was demonstrated to reverse HuR-mediated activation. Mutational and RNA-interference evidence also supports an AUF1 (AU-factor-1, HNRNPD, HGNC:5036) contribution to the observed repressive activity of the 3'UTR in mesenchymal cells. A limited number of studies describe how miRNAs interact with ARE-binding proteins that bind adjacent sites. This study is among the first to describe protein/miRNA interactions at the same site.