Cellular reprogramming is driven by widespread rewiring of promote-enhancer interactions

Interactions between promoters and cis-regulatory elements, such as enhancers, play a role in gene regulation. However, the role of three-dimensional (3D) chromatin structure in orchestrating changes in transcription during cell fate transition is not fully understood. Here, we performed integrated analyses of chromosomal architecture, epigenetics and gene expression using Hi-C, promoter Capture Hi-C (PCHi-C), ChIP sequencing, and RNA sequencing during trans-differentiation of preB cells into macrophages with a ß-estradiol inducible CEBPa-ER transgene. Within 1 hour of ß-estradiol induction, CEBPa translocates from the cytoplasm to the nucleus and binds to thousands of promoters and putative regulatory elements, resulting in downregulation of preB cell specific genes and induction of macrophage specific genes. Hi-C results were remarkably consistent throughout transinduction, revealing only a small number of TAD boundary location changes, and A/B compartment switches despite changes in expression of thousands of genes. PCHi-C reveals changes in promoter-anchored loops with decrease in interactions parallel with their decreased expression, and new promoter-anchored interactions with macrophage specific genes concordant with their increased expression.Overall, our data demonstrate that CEBPa-induced transinduction involves few changes in genome architecture that are detectable by Hi-C, and widespread reorganization of thousands of promoter anchored loops with PCHi-C that drive changes in cell identity. Overall design: We performed Hi-C, promoter capture Hi-C (PCHi-C) and RNAseq to investigate the 3D genome organization during transdifferentiation of Pre-B cells to macrophages.