The detailed 3D multi-loop aggregate/rosette chromatin architecture and functional dynamic organization of the human and mouse genomes.

The dynamic three-dimensional chromatin architecture of genomes and the obvious co-evolutionary connection to its function – the storage and expression of genetic information – is still, after ~170 years, a central question of current research. With a systems genomics approach using a novel selective high-throughput chromosomal interaction capture (T2C) technique together with quantitative polymer simulations and scaling analysis of genomic structures and the DNA sequence, we determined the architecture of genomes with unprecedented molecular resolution and dynamic range from single base pair entire chromosomes: for several genetic loci of different species, cell type, and functional states we find a chromatin quasi-fibre exists with 5±1 nucleosome per 11 nm, which folds into 40-100 kbp loops forming aggregates/rosettes which are connected by a ~50 kbp chromatin linker. Polymer simulations using Monte Carlo and Brownian dynamics approaches confirm T2C results and allow to predict and to explain additional experimental findings. This agrees also with novel dynamics information from fluorescence correlation spectroscopy (FCS) analysis of chromatin relaxations in vivo. Beyond, we find a fine-structured multi-scaling behaviour of both the architecture and the DNA sequence, which shows for the first time the tight entanglement between architecture and sequence. Since, T2C allows reaching an optimal combination of resolution, interaction frequency range, multiplexing, and an unseen signal-to-noise ratio at molecular resolution this, hence, opens the door to architectural sequencing of genomes. Additionally, we have reached the level of genome mechanics, i.e. corresponding statistical mechanics and uncertainty principles appear and need to be considered. Hence, we determined the three-dimensional architecture and dynamics of genomes for the first time in a consistent system genomics manner from several angles which are all in agreement as well as additionally also with the heuristics of the research of the last 170 years. This will lead to a detailed understanding of genomes with fundamental new insights and huge novel perspectives for diagnosis and treatment.