Pre-existing chromatin accessibility of switchable repressive compartment delineates cell plasticity

Abstract

Abstract Cell plasticity endows differentiated cells with competence to be reprogrammed to other lineages. While extrinsic factors driving cell identity conversion has been extensively characterized, it remains elusive which intrinsic epigenetic attributes, including high order chromatin organization, delineate cell plasticity. By analyzing the transcription factors-induced transdifferentiation from fibroblasts to hepatocytes, we uncovered contiguous compartment switchable regions (CSRs) as a unique chromatin unit. Specifically, compartment B-to-A CSRs, enriched with hepatic genes, possessed a mosaic status of inactive chromatin and pre-existing and continuous accessibility in fibroblasts. Pre-existing accessibility enhanced the binding of inducible factor Foxa3, which triggered epigenetic activation and chromatin interaction as well as hepatic gene expression. Notably, these changes were restrained within B-to-A CSR boundaries that were defined by CTCF occupancy. Moreover, such chromatin organization and mosaic status were detectable in different cell types and involved in multiple reprogramming processes, suggesting an intrinsic chromatin attribute in understanding cell plasticity.