show Abstracthide AbstractAbstract: A network of interactions between functional DNA elements regulates gene expression in a precise spatio-temporal pattern during development. This regulation is implemented through many-to-many looping interactions of DNA elements mediated by specific transcription factors such as Ctcf, Gata1 and Yy1. We carried out RNA polymerase II ChIA-PET and DNase-seq in Mouse Erythroleukemia (MEL) cells to capture genomewide changes in the resulting chromatin interaction graphs (CIGs) during DMSO-induced hemoglobin activation. We found that the change of interactions in CIGs is positively correlated to the change of a corresponding genes' expression as measured by RNA-seq. DNase footprints and ChIP-seq data indicate that these long-range interactions are controlled through distinct combinations of transcription factors before and after differentiation, with Ctcf or cohesin only mediating half of these interactions, and Gata1 and/or Yy1 interactions accounting for an additional 40% of detected interactions. Strikingly, while Ctcf and Gata1–mediated interactions were enriched in genes involved in erythrocyte differentiation and mitochondrial regulation, Yy1-mediated interactions were enriched for genes involved in RNA processing, translation, and histone remodeling. We further found that about two-thirds of MEL DNA elements with long-range interactions as well 35% of these interactions are conserved in human K562 cells and show similar combinations of factor occupancy. Taken together, our study identifies that a large set of long-range interactions between active enhancers and promoters involving RNA Pol II are mediated by factors other than cohesin and Ctcf in both human and mouse. Overall design: PU.1 ChIP-Seq, RNA-Seq, DNase-Seq, ChIA-PET The 'MEL_foot_1kb_DHS_cohesin_pol2_peak_blacklistfiltered.bed contains the locations and names of the 1kb vertices used to characterize and quantitate the long-range interaction edges between vertices from the ChIA-PET data. It was generated from the hotspot bed file of MEL DNase-seq data. After incorporating anti-pol2 and cohesin ChIP-seq peaks from ENCODE consortium, the merged DNase-seq hotspots and ChIP-seq peaks were expanded to 1kb in order to make the 1kb vertices.