Abstract
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 cis-regulatory regions mediating this regulation, remain poorly defined. With this in mind, we sought to identify the Bmp3 promoter in mouse (M. musculus) through functional and comparative genomic analyses. We found that the minimal promoter required for expression in resides within 0.8 kb upstream of Bmp3 in a region that is highly conserved with rat (R. norvegicus). 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 Bmp3 upstream ECR, suggesting that this region may preserve common cis-regulatory elements that govern Bmp3 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.
Highlights
The Bone Morphogenetic Protein (BMP) pathway is a signaling cascade that has ancient origins in the evolution of animals, arising 1.2–1.4 billion years ago [1,2]
This pattern was present in every eutherian mammal in our cohort (15/15), but in neither of the non-eutherian mammals, M. domestica and O. anatinus (Figure 3D and Table S3), nor in any of the twenty-two non-mammalian Reference Sequence (RefSeq) genomes (JWL, data not shown). These findings suggested that all or a portion of the distal block conserved between M. musculus and R. norvegicus upstream of Bmp3 is an evolutionary conserved region (ECR) among eutherian mammals
Setting our threshold at 77% identity across a sliding 350 nt window to pinpoint lengthy, highly conserved ‘‘CoreECRs’’ [63], we identified a 505 nt region in M. musculus spanning from position 21642 to 21138 upstream of the Bmp3 transcription start site that is within the distal block conserved between M. musculus and R. norvegicus (Figure 4A)
Summary
The Bone Morphogenetic Protein (BMP) pathway is a signaling cascade that has ancient origins in the evolution of animals, arising 1.2–1.4 billion years ago [1,2]. Canonical BMP signaling occurs through BMP ligand interaction with a complex of type I and type II BMP receptors, leading to activation of a class of downstream transcription factors (SMADs in vertebrates, MAD in Drosophila, SMA in C. elegans). This basic mechanism is highly conserved across all animals [2] and, as no non-animal counterparts have been identified, the BMP pathway is likely a key advancement in the evolution of animals. Extracellular antagonists that sequester BMP ligands away from BMP receptors (eg, Noggin) and E3ubiquitin ligases (eg, SMURF1) that promote degradation of BMP receptors and SMADs [6,7] are ancestral mechanisms for reducing BMP pathway activation that are conserved as early as sponges [2]
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