Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation [IV]
During intestinal organogenesis, equipotent epithelial progenitors mature into phenotypically distinct stem cells that are responsible for life-long maintenance of the tissue. While the morphological changes associated with the transition are well-characterized, the molecular mechanisms underpinning the maturation process are not fully understood. Here, we leverage intestinal organoid cultures to profile transcriptional, chromatin accessibility, DNA methylation and 3D chromatin conformation landscapes in fetal and adult epithelial cells. We observed prominent differences in gene expression and enhancer activity, which are accompanied by local changes in 3D organization,  DNA accessibility and methylation, between the two cellular states. Using integrative analyses, we identified sustained YAP transcriptional activity as a major gatekeeper of the immature fetal state. We found the YAP-associated transcriptional network to be regulated at various levels of chromatin organization, and likely to be coordinated by changes in extracellular matrix composition. Altogether, our work highlights the value of unbiased profiling of regulatory landscapes for the identification of key mechanisms underlying tissue maturation. Overall design: Profiling of transcription and chromatin accessibility and organisation in E16.5 fetal and adult small intestinal epithelial organoids with CAGE, ATAC-Seq, WGBS, and Hi-C, gene expression profiling of adult crypt proximal small intestinal epithelium, and comparative gene expression profiling of adult intestinal organoid cultures from an inducible TetON-hYAP/H2B-mCherry mouse strain with or without doxycyclin (DOX) induced expression of a constitutively active (S127A mutant) YAP transgene.