Abstract
In mammals, genomic DNA that is roughly 2 m long is folded to fit the size of the cell nucleus that has a diameter of about 10 μm. The folding of genomic DNA is mediated via assembly of DNA-protein complex, chromatin. In addition to the reduction of genomic DNA linear dimensions, the assembly of chromatin allows to discriminate and to mark active (transcribed) and repressed (non-transcribed) genes. Consequently, epigenetic regulation of gene expression occurs at the level of DNA packaging in chromatin. Taking into account the increasing attention of scientific community toward epigenetic systems of gene regulation, it is very important to understand how DNA folding in chromatin is related to gene activity. For many years the hierarchical model of DNA folding was the most popular. It was assumed that nucleosome fiber (10-nm fiber) is folded into 30-nm fiber and further on into chromatin loops attached to a nuclear/chromosome scaffold. Recent studies have demonstrated that there is much less regularity in chromatin folding within the cell nucleus. The very existence of 30-nm chromatin fibers in living cells was questioned. On the other hand, it was found that chromosomes are partitioned into self-interacting spatial domains that restrict the area of enhancers action. Thus, TADs can be considered as structural-functional domains of the chromosomes. Here we discuss the modern view of DNA packaging within the cell nucleus in relation to the regulation of gene expression. Special attention is paid to the possible mechanisms of the chromatin fiber self-assembly into TADs. We discuss the model postulating that partitioning of the chromosome into TADs is determined by the distribution of active and inactive chromatin segments along the chromosome.This article was specially invited by the editors and represents work by leading researchers.
Highlights
The concept of hierarchic chromatin organization in the eukaryotic cell nucleus has been developed rather long ago and is commonly accepted [1,2,3]
We studied the distributions of several insulator proteins relative to Topologically associating domain (TAD) boundaries in four Drosophila cell lines of different origins and did not detect an appreciable enrichment in binding sites for dCTCF and Su(Hw) for TAD boundaries [44]
Our current results strongly suggest that, in Drosophila, inactive chromatin domains became assembled in compact masses (TADs) due to electrostatic interaction of nucleosomes located on neighboring fibers [44]
Summary
The concept of hierarchic chromatin organization in the eukaryotic cell nucleus has been developed rather long ago and is commonly accepted [1,2,3]. The above results do not contradict the mere existence of higher-order hierarchic levels in chromatin compaction, but indicate that these levels are not based on assembly of regular structures, such as the 30-nm fiber. An important contribution to understanding the principles of hierarchic chromatin folding was made in studies that employed the so-called C methods, which address the physical proximity of particular genome regions in the threedimensional space of the cell nucleus. A Hi-C method assesses the physical proximity of various DNA fragments on a genome-wide scale and is the most informative for analyzing the general principles of chromatin folding [34] Studies with this experimental technique provided independent experimental support to the existence of chromosome territories [34], which were earlier detected by confocal microscopy of nuclei stained with sets of chromosome-specific hybridization. A main feature of TADs is that intra-TAD spatial contacts between genome elements are significantly more frequent
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