Long-range gene regulation, genomics, developmental biology, bone and joint development
How does the genome encode instructions that guide embryonic development? Our research uses genes that are expressed during vertebrate development as systems for investigating this question. We have two long-term goals. The first is to shed light on regulatory events driving bone and cartilage development. This is relevant to understanding birth defects, osteoporosis and arthritis. The second is to locate and understand the function of long-range genomic sequences that control gene regulation. These sequences can act across hundreds of kilobases and are often well conserved. We study these elements using tools such as BAC (Bacterial Artificial Chromosome) transgenesis and genomic sequence comparisons.
Much of our progress has been based on three BMP (Bone Morphogenetic Protein) family genes. All are transcribed in complex patterns during development. Precise regulation of these genes is controlled by multiple, distant cis-regulatory elements. Using transgenic assays in mice and zebrafish, we are charting out the location of many cis-regulatory elements that are spread across hundreds of kilobases around these genes. These genes are: Gdf6, which is required for patterning a subset of limb, skull and other skeletal joints during embryonic development; and Bmp2 and Bmp4, both of which are important in bone formation and many sites of organogenesis. Interestingly, each gene is flanked by large ?gene deserts? that contain strongly conserved noncoding sequences, some of which are long-distant regulatory elements. These projects are relevant to understanding the role of noncoding sequences in development and for evolution of skeletal morphology.
Currently, we are investigating the role of BMP2 regulation as a key potential mediator of calcific aortic valve disease (CAVD). BMP2 impacts this disease at 2 stages: first, in the embryo, during heart valve formation; and second, when it is upregulated in the adult aortic valve and likely stimulates the calcification of valve tissue. Along with our collaborator Dr. Melissa Rogers (Rutgers) we are determining the pre- and pos-transcriptional regulatory pathways that control BMP2 in the heart.