Kinetics of transcriptome during hepatic conversion [RNA-seq]

Cell plasticity endows differentiated cells with competence to be reprogrammed to other identities. While reprogramming factors-induced epigenetic changes have been characterized, intrinsic chromatin features underlying cell plasticity remain elusive. By characterizing kinetics of high-order chromatin structures during transdifferentiation from fibroblasts to hepatocytes, we identified contiguous compartment switchable regions (CSRs). Compartment B to A CSRs (B-to-A CSRs), enriched with hepatocyte genes and demarcated by loop anchors, displayed a chimeric status of pre-existing chromatin accessibility in repressive compartment in fibroblasts. Pre-existing accessibility allowed the occupancy of pioneer factor Foxa3 to B-to-A CSRs, triggering compartment switch, H3K27ac gain and H3K27me3 reduction, and hepatocyte gene activation. Moreover, chimeric chromatin status appeared to be related with fibroblasts reprogramming to neurons, cardiomyocytes and pluripotent stem cells. Together, pre-existing accessibility in compartment B defines a chimeric chromatin status that may constitute intrinsic attribute for cell plasticity. Overall design: Examination of chromatin structures by Hi-C, chromatin status by ATAC-seq, H3K27ac and H3K27me3 ChIP-seq and transcriptome by RNA-seq. Examination of protein binding of Foxa3, Gata4, Hnf1a and CTCF by CHIP-seq. Hi-C, ATAC-seq and RNA-seq were performed with replicates for each time point in our study.