Dynamic transcriptional and epigenetic changes define postnatal tendon growth.

Tendons are dynamic structures that efficiently transmit force and enable movement. From birth, tendons undergo dramatic changes from a principally cellular tissue to a hypocellular one characterized by a dense and highly ordered extracellular matrix. During this time, tendon cells change morphology from rounded to stellate in appearance and their proliferative rates decline. Significant expansion and maturation of the extracellular matrix (ECM) grow the tendons in length and diameter and alter their biomechanical properties to sustain increased physical activities. Surprisingly, for such an important stage of tendon maturation, we understand very little about the transcriptional and epigenetic regulators that direct these processes. Here, we present a roadmap of genes that are differentially regulated during the early neonatal and postnatal time period. We find differentially expressed genes fall into specific transcriptional modules, representing expression increases, decreases, or gene sets undergoing dynamic changes over postnatal time. By pairing our transcriptomic data with epigenetic data, we performed an integrative analysis of the datasets and further defined modules with highly correlated changes in gene expression and chromatin accessibility. From this analysis, several new pathways emerge. Among them, we focus on Yap1, a transcriptional co-activator of the Hippo signaling pathway. We observe accessible regions near to differentially expressed genes, containing motifs for TEAD, the transcription factor that binds Yap to regulate transcription. Conditional loss of Yap1 at postnatal stages alters early expression of Col1a1 and matrix organization and density but does not affect gross ultrastructural and mechanical properties at later stages. Together, our analyses identify a regulator of early matrix formation and provides a rich dataset with which to interrogate transcriptional networks and pathways during this poorly understood time in tendon growth.