Identification of candidate regulatory elements controlling transcriptome during the formation of interphalangeal joints.

摘要: Formation of the synovial joint starts with the visible emergence of interzone, a stripe of densely packed mesenchymal cells located between distal ends of the developing skeletal anlagen. Recently the transcriptome of the early synovial joint was reported. Knowledge about regulatory elements such as enhancers would complement these data and lead to a better understanding of the genetic control of gene transcription at the onset of joint development. Using ChIP-sequencing we have mapped the H3 signatures H3K27ac and H3K4me1 to locate the regulatory elements specific for the interzone and adjacent phalange, respectively. This atlas of candidate enhancers (CEs) was then used to map the association between these respective joint tissue specific CEs and biological processes. Subsequently, an integrative analysis of transcriptomic data and CEs identified new putative regulatory elements of genes expressed in interzone (eg GDF5, BMP2 and DACT2) and phalange (eg MATN1, HAPLN1 and SNAI1). We also linked such CEs to genes characterized as crucial in synovial joint hypermobility and osteoarthritis, as well as phalange malformations. These analyses show that the enhancer atlas can serve as resource for identifying putative disease-causing genomic regulatory regions in patients with synovial joint dysfunctions and/or phalange disorders, and enhancer-controlled synovial joint and phalange formation.