The formation of chromatin domains involves a primary step based on the 3-D structure of DNA

The general model presented here for the formation of chromatin domains, LADs and TADs, is primarily based on the 3-D structures of the corresponding DNA sequences, the GC-poor and GC-rich isochores. Indeed, the low-heterogeneity GC-poor isochores locally are intrinsically stiff and curved because of the presence of interspersed oligo-Adenines. In contrast, the high-heterogeneity GC-rich isochores are in the shape of peaks characterized by increasing levels of GC and of interspersed oligo-Guanines. In LADs, oligo-Adenines induce local nucleosome depletions leading to structures that are well suited for the attachment to (and embedding in) the lamina. In TADs, the gradients of GC and of oligo-Guanines are responsible for a decreasing nucleosome density, decreasing supercoiling and increasing accessibility. This “moulding step” shapes the “primary TADs” into loops that lack self-interactions, being CTCF/cohesin-free structures. The cohesin complex then binds to the tips of “primary TADs” and slides down the loops, thanks to Nipbl, an essential factor for loading cohesin and for stimulating its ATPase activity and its translocation. This “extruding step” leads to closer contacts and to self-interactions in the loops and stops at the CTCF binding sites located at the base of the loops that are thus closed and insulated.