Chromatin has a complex spatial organization in the cell nucleus that serves vital functional purposes. A variety of chromatin folding conformations has been detected by single-cell imaging and chromosome conformation capture-based approaches. However, a unified quantitative framework describing spatial chromatin organization is still lacking. Here, we explore the "strings and binders switch" model to explain the origin and variety of chromatin behaviors that coexist and dynamically change within living cells. This simple polymer model recapitulates the scaling properties of chromatin folding reported experimentally in different cellular systems, the fractal state of chromatin, the processes of domain formation, and looping out. Additionally, the strings and binders switch model reproduces the recently proposed "fractal-globule" model, but only as one of many possible transient conformations.genome organization | genome architecture | long-range chromatin interactions | fluorescence in situ hybridization | Monte Carlo simulations U nderstanding the interplay between genome architecture and gene regulation is one of the most challenging problems in biology. During mitosis, chromosomes are found in a condensed state, but decondense during interphase, when highly coordinated cellular processes such as transcription, DNA repair, and replication take place, creating cell-type-specific chromatin folding (1-3).Chromosome organization occurs at different scales of genomic length to yield variable degrees of compaction (4). Linear nucleosome arrays fold into higher-order structures, first through local chromatin interactions, such as between promoters and enhancers, and then eventually giving rise to discrete chromosome territories (1).Spatial genome organization is guided by intra-and interchromosomal interactions mediated by nuclear components that include transcription factors, transcription and replication factories, Polycomb bodies, and contacts with the lamina (5-8). However, how binding of diffusible factors to specific genomic regions drives chromatin folding remains poorly understood.Imaging of single loci by FISH and genome-wide mapping of chromatin interactions by chromosome conformation capture (3C) approaches revealed a variety of chromatin architectures across genomic regions and cell types, and upon environmental cues (9-14) (Fig. S1A). In FISH experiments, chromatin folding is often measured by the mean-square spatial distance, R 2 ðsÞ, between two genomic regions as a function of their linear genomic distance, s (Fig. S1B), which usually exhibits scaling properties R 2 ðsÞ ∼ s 2v . Although the behavior of R 2 ðsÞ appears to depend on the genomic regions and cell types assessed (Fig. S1A), in general, at large genomic distances, R 2 ðsÞ reaches a plateau (i.e., v ¼ 0) that reflects the folding of chromosomes into territories (15).A global analysis of genome-wide 3C (Hi-C) ligation products in human cells averaged across all chromosomes has been used to estimate the "contact probability," P c ðsÞ (13). Th...

SummaryThe organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. We developed a novel genome-wide method, Genome Architecture Mapping (GAM), for measuring chromatin contacts, and other features of three-dimensional chromatin topology, based on sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify an enrichment for specific interactions between active genes and enhancers across very large genomic distances, using a mathematical model ‘SLICE’ (Statistical Inference of Co-segregation). GAM also reveals an abundance of three-way contacts genome-wide, especially between regions that are highly transcribed or contain super-enhancers, highlighting a previously inaccessible complexity in genome architecture and a major role for gene-expression specific contacts in organizing the genome in mammalian nuclei.