Dynamics of long-range gene regulation at the BMP2 locus

Abstract

A member of the TGF-â superfamily of cytokines, BMP2 not only plays a critical role in pattern formation and morphogenesis during early embryonic development, but also promotes osteoblast differentiation and bone formation, making it a vital factor for the maintenance of bone health. Expanding on earlier studies of the regulatory landscape surrounding Bmp2 by BAC transgenesis in mice that had lead to the identification of the osteoblast enhancer ECR1, the work presented here further scrutinizes the particular role of ECR1 during osteogenesis and provides striking evidence for the hypothesis that – despite its indispensable role for Bmp2 expression in osteoblasts -, it is in fact not entirely autonomous, but requires additional enhancer activity to control the full scope of osteoblast-specific expression. Subsequent analysis of the chromosomal conformation during transcriptional activation does not only support this hypothesis and substantiate the dynamic nature of looping interactions at the locus, but combined with additional epigenetic characteristics also serves to highlight several distant loci within the gene desert as excellent candidates for putative enhancer function.