Abstract
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.
Highlights
Fifty years ago, well before any sequencing technique was available, a new approach, later called compositional genomics, was developed in order to understand the organization of the mammalian genome
The original investigation[2] concerned two satellite DNAs, that appeared in CsCl density gradient ultracentrifugation experiments as unresolved shoulders on the “main band” DNAs of mouse and guinea pig, respectively, and that were completely separated by ultracentrifugation in Cs2SO4/Ag+ gradients
The separation was possible because of the differential binding of silver ions on the short repeats of the satellite DNAs and led to the conclusion that satellites DNA are “conformationally slightly different” from main-band DNA, the differences being related to their particular nucleotide sequences[2]
Summary
Well before any sequencing technique was available, a new approach, later called compositional genomics, was developed in order to understand the organization of the mammalian genome This approach was based on the “short-sequence designs”[1] of DNA molecules. When the Cs2SO4/Ag+ was applied to the bovine genome, the standard mammalian genome at that time, several cryptic satellite DNAs were revealed, but, much more importantly, the “main band” DNA molecules were resolved into three families or “major components”[4] This was the first evidence that, neglecting satellites, the genome consisted of large DNA regions that differed in the frequency of short-sequence binding sites for silver ions and of short-sequences split by DNAses. A work still in press showed that the isochores of Drosophila[20] correspond to TADs21
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
