The landscape of global long-range interactions in human erythroid cells mediated by GATA1 and CTCF during differentiation

A network of long-range interactions between functional DNA elements regulates gene expression in a precise spatio-temporal pattern during development. We carried out anti-RNA polymerase II and cohesin ChIA-PET and DNase-seq in Mouse Erythroleukemia (MEL) cells to capture genome-wide changes between open chromatin elements in chromatin interaction graphs (CIGs) during DMSO-induced hemoglobin activation. We found that the change of interaction strength in CIGs is positively correlated to expression changes in corresponding genes as measured by RNA-seq. DNaseI 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, with GATA1, PU.1 and/or other transcription factorsYY1 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, PU.1YY1-mediated interactions were enriched for genes involved in RNA processing, cell cycletranslation, and chromatin organizationhistone remodeling. We further found that two-thirds of MEL DNA elements with long-range interactions as well as 35% of their interactions are conserved in human K562 cells and they show similar combinations of factor occupancy in both species. Our study highlights the importance of quantitative analysis of changes in long-range interaction strengths in quantifying changes in gene expression. Overall design: MELs grown to a density of 1 million/ml were differentiated using 2% DMSO (VWR) added to the medium and the cells were grown for another 5 days to induce the expression of hemoglobin genes. Biological replicates of anti-SMC1 (subunit of cohesin complex) ChIA-PET libraries for uninduced (MEL) and induced (MEL+DMSO) MEL were constructed. Please note that the processed data *new.txt files were generated from both replicates (i.e. R1 and R2 samples) and are linked to the corresponding R1 sample records.