“…Thus, even without invoking “loop extrusion”, binding of proteins (simulated by spheres) to the chromatin fiber (simulated by a string of beads) gives rise to loops. Strikingly, chromatin‐bound factors of the same “identity” will cluster spontaneously to form multi‐loop structures that explain much of the structure seen in TADs and/or A‐/B‐compartments (Barbieri et al , ; Brackley et al , , ). Of course, this requires both multivalency and “on/off” binding cycles from the protein factor with a propensity to rebind the same cluster (as seen for Sox2 by live cell imaging; Liu et al , ), and it appears that much of the information required for the proper spatial folding of chromosomes is encoded in the epigenetic profiles marking their active and inactive stretches (Di Pierro et al , ), and even pure mechanical forces can profoundly impact both epigenetic and higher order characteristics of chromosomes (Le et al , ; Stephens et al , ).…”