Erf chromatin binding-sites in E13.5 mouse embryo fibroblasts

We show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 , causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf reduced to ~30% of normal exhibit postnatal multisuture synostosis; by contrast, embryonic calvarial development appears mildly delayed. Using chromatin immunoprecipitation in mouse embryonic fibroblasts and high-throughput sequencing, we find that ERF binds preferentially to distal regulatory elements containing RUNX or AP1 motifs. This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes. Examination of Erf binding site in E13.5 mouse embryo fibroblasts, growing in the presence or absence of serum for 4 hours