Creb5 controls its own expression and directly induces the joint-interzone regulatory program [RNAseq_Prx1]

Our prior work indicated that the transcription factor Creb5 plays a crucial role in the genesis of synovial joints. Here, we perform an integrative analysis of the transcriptome, chromatin accessibility, and Creb5-chromatin occupancy in Creb5-expressing synovial joint progenitor cells. This analysis revealed that Creb5 directly binds to both its own two promoters and to the regulatory regions of the early joint markers, Gdf5 and Sfrp2; each of whose expression in the joint-interzone is Creb5-dependent. Functional enhancer analysis indicated that Creb5 binding sites in its own two promoters are necessary for these sequences to drive transgene expression in a pattern that mimics endogenous Creb5 expression. While Creb5 directly regulates both Gdf5 and Sfrp2 expression in the inner joint-interzone by binding to either CREs or TREs in their regulatory elements, Creb5 activates Barx1 expression specifically in the outer joint-interzone; and thus initiates both the formation of the joint-interzone and regionalization of cell fates within this tissue.