Control of BMP gene expression by long-range regulatory elements

Abstract

Much evidence suggests that "developmental regulator" genes, like those encoding transcription factors and signaling molecules, are typically controlled by many modular, tissue-specific cis-regulatory elements that function during embryogenesis. These elements are often far from gene coding regions and promoters. Bone morphogenetic proteins (BMPs) drive many processes in development relating to organogenesis and differentiation. Four BMP family members, Bmp2, Bmp4, Bmp5, and Gdf6, are now known to be under the control of distant cis-regulatory elements. BMPs are thus firmly placed in the category of genes prone to this phenomenon. The analysis of distant BMP regulatory elements has provided insight into the many pleiotropic effects of BMP genes, and underscores the biological importance of non-coding genomic DNA elements.

Figure 1. Gene deserts around the human BMP2, BMP4 and GDF6 genes

Shown are UCSC genome browser plots of roughly 3 megabases of DNA surrounding each gene and all annotated (RefSeq) genes. The yellow shading indicates “gene deserts” around or adjacent to each BMP gene. The gene deserts are similarly-sized in the mouse genome, and each gene desert has extensive regions of noncoding cross-species conservation (not shown).

Figure 2. Schematic diagram of the cis-regulatory landscape surrounding the mouse Bmp2 and Bmp4 genes

Shown is a summary of the locations of important cis-regulatory features that have been identified to date for Bmp2 and Bmp4. The colored horizontal bars represent large domains that were shown by BAC transgenesis to contain elements driving expression in the indicated tissues. Smaller domains that were tested for enhancer activity are shown as upright ovals. SNPs with significant correlations to human disease and development are highlighted by dashed boxes. Promoter regions that have been tested for ability to drive reporter gene expression in vivo are shown as purple boxes. Red arrows correspond to the coding sequences for Bmp2 and Bmp4.