Comparative Genomics Identifies the Mouse <em>Bmp3</em> Promoter and an Upstream Evolutionary Conserved Region (ECR) in Mammals

<div><p>The Bone Morphogenetic Protein (BMP) pathway is a multi-member signaling cascade whose basic components are found in all animals. One member, BMP3, which arose more recently in evolution and is found only in deuterostomes, serves a unique role as an antagonist to both the canonical BMP and Activin pathways. However, the mechanisms that control BMP3 expression, and the <i>cis</i>-regulatory regions mediating this regulation, remain poorly defined. With this in mind, we sought to identify the <i>Bmp3</i> promoter in mouse <i>(M. musculus</i>) through functional and comparative genomic analyses. We found that the minimal promoter required for expression in resides within 0.8 kb upstream of <i>Bmp3</i> in a region that is highly conserved with rat (<i>R. norvegicus</i>). We also found that an upstream region abutting the minimal promoter acts as a repressor of the minimal promoter in HEK293T cells and osteoblasts. Strikingly, a portion of this region is conserved among all available eutherian mammal genomes (47/47), but not in any non-eutherian animal (0/136). We also identified multiple conserved transcription factor binding sites in the <i>Bmp3</i> upstream ECR, suggesting that this region may preserve common <i>cis</i>-regulatory elements that govern <i>Bmp3</i> expression across eutherian mammals. Since dysregulation of BMP signaling appears to play a role in human health and disease, our findings may have application in the development of novel therapeutics aimed at modulating BMP signaling in humans.</p>