ELUCIDATION OF THE GENE REGULATION NETWORK CONTROLLING EMBRYONIC SKELETAL DEVELOPMENT

Abstract

Developmental skeletal disorders such as cleidocranial dysplasias can be more effectively addressed if we can map the molecular mechanisms underlying bone development into a gene regulatory network. Runx2 plays a major role in osteoblast differentiation and regulates chondrocyte maturation with Runx3, in a redundant manner. By coupling mouse transgenic techniques with high throughput genomic studies such as gene expression profiling and ChIP-Seq, gene expression profiles for Runx2 and Runx3 using an enriched pool of Runx2- and/or Runx3-expressing cells isolated from fluorescing mouse embryos were generated. Additionally, Runx2-specific binding sites were mapped using HA3-tagged mouse embryos and anti-HA antibody to identify Runx2 direct targets to complement the expression profiling data. This study is the first to reveal the vast number of factors controlled by both Runx2 and Runx3 cooperatively, antagonistically and uniquely, thus establishing a preliminary gene regulatory network centered around the Runx2 and Runx3 transcription factors.