Genome-wide coherence between enhancer states and 3D chromosome conformation in mouse T cell differentiation

Complex genomes are intricately organised in 3D nuclear space, yet the extent to which genome form and function are interconnected remains subject to intense debate. To elucidate this relationship, we generated developmental stage-specific maps of enhancer state, gene expression, and chromosome conformation during CD4 T cell differentiation. While progression from the DP to the CD4 SP stage of thymocyte differentiation was accompanied by activation and repression of hundreds of genes and enhancers, Hi-C maps of DP and CD4 SP were visually highly similar, and discrete Hi-C measures such as TADs, contact domains, loops, or compartments failed to unambiguously link genome organisation to gene regulatory activity. At face value, these findings appear to support proposals of a disjoint between genome form and function. By contrast, Twins, a deep learning approach trained to distinguish technical from biological variation in Hi-C data, revealed compelling coherence between gene regulatory changes and genome organisation. Analysis of local Hi-C contacts demonstrated that the strength of Hi-C contacts quantitatively reflected developmental stage-specific enhancer states. These findings demonstrate correspondence between genome form and function in mouse T cell differentiation, and suggest a rationale for the control of gene expression by distal regulatory elements. Overall design: Chromatin contact profiles in wild type or CTCF/Rad21 double knockout cells were generated by in situ Hi-C. Chromatin contact profiles in control or enhancer insertion cells were generated by capture Hi-C. Examination of enrichment of total H3 and H3K27ac in primary cells by ChIP-seq.