Abstract
Chromatin folding inside the interphase nucleus of eukaryotic cells is done on multiple scales of length and time. Despite recent progress in understanding the folding motifs of chromatin, the higher-order structure still remains elusive. Various experimental studies reveal a tight connection between genome folding and function. Chromosomes fold into a confined subspace of the nucleus and form distinct territories. Chromatin looping seems to play a dominant role both in transcriptional regulation as well as in chromatin organization and has been assumed to be mediated by long-range interactions in many polymer models. However, it remains a crucial question which mechanisms are necessary to make two chromatin regions become co-located, i.e. have them in spatial proximity. We demonstrate that the formation of loops can be accomplished solely on the basis of diffusional motion. The probabilistic nature of temporary contacts mimics the effects of proteins, e.g. transcription factors, in the solvent. We establish testable quantitative predictions by deriving scale-independent measures for comparison to experimental data. In this Dynamic Loop (DL) model, the co-localization probability of distant elements is strongly increased compared to linear non-looping chains. The model correctly describes folding into a confined space as well as the experimentally observed cell-to-cell variation. Most importantly, at biological densities, model chromosomes occupy distinct territories showing less inter-chromosomal contacts than linear chains. Thus, dynamic diffusion-based looping, i.e. gene co-localization, provides a consistent framework for chromatin organization in eukaryotic interphase nuclei.
Highlights
The cell nucleus is a main constituent of eukaryotic organisms and yet its complexity prevents detailed knowledge of its function
Mean square distance between chromatin segments We first show that the Dynamic Loop model is in agreement with experimental data from fluorescence in situ hybridization (FISH) measurements [12,40], which provide information about the relative physical distance between two target sites
Our results suggest that even large loops can arise without active transport mechanisms
Summary
The cell nucleus is a main constituent of eukaryotic organisms and yet its complexity prevents detailed knowledge of its function. While during mitosis chromosomes are found in an extremely condensed state, the chromatin fiber inside the interphase nucleus has a much more decondensed organization. At this stage of the cell cycle, highly coordinated processes such as transcription, replication and DNA repair take place, making a random folding of the chromatin fiber very unlikely. The organization of the genome in the interphase nucleus of eukaryotic cells is done on multiple scales of length and degrees of compaction. The chromatin fiber is a complex of nucleosomes and linker DNA forming a beads-on-a-string type of filament with a diameter of about 11 nm [1]. Labeling two loci of a chromosome with a fluorescent marker was successfully used to establish a relationship between genomic distance g between these markers and its mean square physical distance in yeast [8], drosophila [9,10] and human cells [11,12]
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