Cohesin distribution alone predicts chromatin organization in yeast via conserved-current loop extrusion.

Abstract

Inhomogeneous patterns of enhanced chromatin-chromatin contacts within 10-100 kb-sized regions of the genome are a generic feature of chromatin spatial organization. These features, termed topologically associating domains (TADs), have led to the loop extrusion factor (LEF) model, where TADs arise from loop extrusion by cohesin complexes. Currently, our ability to model TADs relies on the observation that in vertebrates TAD boundaries are correlated with DNA sequences that bind CTCF, which therefore is inferred to block loop extrusion. However, although TADs feature prominently in their Hi-C maps, non-vertebrate eukaryotes either do not express CTCF or show few TAD boundaries that correlate with CTCF sites. In all of these organisms, the counterparts of CTCF remain unknown, frustrating comparisons between Hi-C data and simulations. To extend the LEF model across the tree of life, here, we propose the conserved-current loop extrusion (CCLE) model that interprets loop-extruding cohesin as a nearly-conserved probability current. From cohesin ChIP-seq data alone, we thus derive a position-dependent loop extrusion rate, allowing for a modified paradigm for loop extrusion, that goes beyond solely discrete, localized barriers to also include loop extrusion rates that vary more continuously across the genome. To demonstrate its utility in organisms lacking CTCF, we applied the CCLE model to the Hi-C maps of interphase Schizosaccharomyces pombe, as well as to those of meiotic and mitotic Saccharomyces cerevisiae. In all cases, even though their Hi-C maps appear quite different, the model accurately predicts the TAD-scale Hi-C maps. It follows that loop extrusion by cohesin is indeed the primary mechanism underlying TADs in these systems. CCLE allows us to obtain loop extrusion parameters such as the LEF density and processivity, which compare well to independent estimates. The model also provides new insights into in vivo LEF composition and function.