Gene expression is a complex multilevel process that involves various functional units, from nucleosomes to fully formed chromatin fibers accompanied by a host of various chromatin binding enzymes. 1 An integrated understanding of the structural and functional aspects of epigenetics with nuclear architecture during the differentiation of toti- or pluripotent cells to functionally distinct cell types is required to understand the dynamics of gene regulation and expression. 5
A typical higher eukaryotic cell contains ∼2 m of DNA that must be packed into a nucleus ∼10 µm in diameter. Assuming approximately five trillion cells in the human body, the total amount of DNA in an individual is on the order of 10 trillion meters—the equivalent of spanning the distance from Earth to Sun more than 100 times! Clearly, cells face a tremendous challenge to ensure the safekeeping and accurate propagation of DNA during replication and cell division, at the same time allowing accessibility of regulatory factors to genes at the right time and in the right place. Despite the extraordinary length of DNA in a cell, it is noteworthy that DNA-containing chromatin only takes up an estimated 15% of the nuclear volume. To accommodate the immense length of DNA in the nucleus and to ensure functionality, the genetic material is wrapped into higher-order chromatin fibers culminating in the organization of chromatin into chromosome territories. A chromosome territory is the physical space taken up by a given chromosome in the interphase nucleus. The territorial organization of chromosomes in interphase (chromosome territories, CTs) constitutes a basic feature of nuclear architecture. 6
A global view of the cell nucleus.
Chromatin domain folding is determined by transcriptional activity of genome regions. Boundaries form at the interface of active and inactive parts of the genome. Higher-order domains of similar activity status cluster to form chromatin domains, which assemble into chromosome territories. Repressive regions of chromosomes tend to contact other repressive regions on the same chromosome arm, whereas active domains are more exposed on the outside of chromosome territories and have a higher chance of contacting active domains on the other chromosome arm and on other chromosomes, giving rise to topological ‘superdomains’ composed of multiple, functionally similar genome domains. The location of territories is constrained by their association with the nuclear periphery, transcription hubs, nuclear bodies and centromere clusters. 7
Transcription and gene regulation Genome topology has emerged as a key player in all genome functions. Although a contribution of local genome looping in transcription has long been appreciated, recent observations have revealed the importance of long-range interactions, and genome-wide studies have uncovered the universal nature of such regulatory genome topology interactions in gene regulation. Several types of chromosomal interactions, either in the form of loops between sequences on the same chromosomes or interchromosomal interactions, have emerged as key mechanisms in gene regulation.
The nature of genome topology is very precise, and so its regulatory functions in gene expression and genome maintenance. The emerging picture is one of extensive self-enforcing feedback between activity and spatial organization of the genome, suggestive of a self-organizing and self-perpetuating system that uses epigenetic dynamics to regulate genome function in response to regulatory cues and to propagate cell-fate memory 7
The three-dimensional (3D) spatial position of genomic regions during interphase is an important factor linking chromatin architecture with gene expression regulation. Interphase chromosomes are arranged in chromosome territories (CTs) which occupy specific regions of a nucleus 4 Studies indicate that nuclear architecture is correlated with and underlines gene expression. Phenotypic consequences are the result of altering the 3D genome organisation particularly in relation to early development (and pluripotency).
Chromatin is not only a necessary mean to compact this huge amount of DNA in a small nucleus, but also an integrant part of the regulation of all cellular functions using DNA as a template. The multi-layered compartmentalization of chromatin allows for a more efficient gene expression and chromatin conformation regulation as DNA binding factors associated with a certain function will be addressed to a specific nuclear location. Hence, they will find their target faster and will be able to coordinate the expression of multiple genes involved in one specific biological pathway.
More than a thousand proteins interact with or are directly a part of chromatin structure.
DNA flows inside a cell's nucleus in a choreographed line dance. 2 Molecular machines along the DNA cause segments of the chromatin to straighten and pull taut. This activity aligns neighbouring strands to face the same direction. That alignment, in turn, results in a cascading waltz of genetic material shimmying across the nucleus. The dancing DNA may play a role in gene expression, replication and remodelling.
Our genome is amazingly dynamic: While the cell is working, the DNA strands and their packaging wind their way around the cell nucleus. They almost seem to dance. Researchers have now elucidated what lies behind the dynamics of chromatin. As their analyses reveal, the seemingly chaotic dance of chromatin has a method: whenever enzymes unfold the DNA at a particular point and prepare it for reading, this generates liquid streams that also arrange the neighbouring strands in parallel. If the chromatin contracts again, the strands continue to "dance" in disorder.
There are two ways a molecular machine along a DNA molecule might move nearby genetic material: pulling and pushing. A molecular machine can't exert a net force, which means that by pulling on one piece of DNA, it must hold onto and pull something else. The two inward-pulling forces will cancel, giving zero net force and causing the DNA segment to contract. If the machine instead pushes outward, the forces will similarly cancel, and the DNA segment will extend. This DNA shimmy helps distribute throughout the nucleus the molecular machinery responsible for expressing a particular gene.
These contractions and extensions take place within a gooey liquid that fills a cell's nucleus. The movement of the DNA generates a flow in the liquid that can reorient nearby lengths of molecules. It's like the cell pre-programming directs part of the nucleus suddenly to go and move over a certain way a little, then another bit or directs all going to move over another way. The chromatin is sort of directed, oriented, or guided to wander around.
Chromatin is a very flexible mechanically coupled extended polymer in a confined fluidic environment moving under dipolar forces created by the activity of tethered motors. A tether is a cord, fixture, or flexible attachment that anchors something movable to a reference point which may be fixed or moving.
It is when the resulting active dipoles are extensile that large-scale coherent motion is observed, and the emergence of this coherence is intimately related to nonlocal chain stretching and alignment driven by hydrodynamics. Hydrodynamic interactions between dipolar forces alone can lead to the large-scale coherent motion observed in vivo, it is conceivable that electrostatic as well as van der Waals interactions might contribute to the effective amplitude of dipolar forces at short length scales (e.g., the epigenetic code at the nucleosome level).
In interphase, time between two cell divisions, chromatin fills the cell nucleus in its minimally condensed polymeric state. 3 Chromatin serves as substrate to a number of biological processes, e.g. gene expression and DNA replication, which require it to become locally restructured. These are energy-consuming processes giving rise to non-equilibrium dynamics. Regions of coherent motion extended beyond the boundaries of single-chromosome territories, suggesting elastic coupling of motion over length scales much larger than those of genes.
Post-transcriptional modifications (PTMs) of histones affect gene transcription
In addition to nonspecific physical interactions, proteins involved in chromatin remodelling (e.g., SWI/SNF and ISWI)
Distortion of histone octamer core promotes nucleosome mobilization by a chromatin remodeler
The establishment of specific gene expression states during the course of development, as well as their maintenance through the disruptive events of transcription, DNA replication, and DNA repair, requires rapid rearrangements of chromatin structure. Adenosine 5´-triphosphate (ATP)–dependent chromatin remodelling motors are the workhorses that enable dynamic changes in chromatin structure. These motors have the formidable task of mobilizing DNA in the context of a nucleosome, which contains ~150 base pairs of DNA tightly wrapped around an octamer of histone proteins. Both the ISWI and SWI-SNF family motors can move DNA without disassembling the histone octamer. Further, recent studies indicate that ISWI family motors translocate DNA out of the nucleosome before feeding DNA into the nucleosome, a result that is difficult to reconcile with rigid Legoblock–like models of the histone octamer. One way the seemingly complex task of chromatin remodelling may be facilitated is by distorting the histone octamer.
The histone core of a nucleosome is more plastic than previously imagined, and octamer deformation can play different roles based on the type of chromatin remodelling complex. 1
Model for role of octamer distortion in nucleosome sliding by SNF2h.
Octamer deformation near SHL2 (inhibited by sCx2 cross-link) promotes initiation of DNA translocation, while deformation near the dyad (inhibited by sCx1 cross-link) helps accommodate strain caused by DNA translocation. These conformational changes allow for a net translocation of DNA from the exit site before any DNA is drawn in from the entry site.
Structural maintenance of chromosomes (e.g., cohesin) could also be affecting the length and time scales of the coherent motions by generating bends, folds, entanglements, or loops in the chromatin fiber.
Chromosome condensation and compaction is nothing short than awe-inspiring, amazing evidence of setup by a supreme intelligence.
A key role seems to be played by nuclear ATPases in driving coherent chromatin motions.
Na+/K+-ATPase are located in the cell nuclei membrane. In addition, there is an overlap between nuclear Na+/K+-ATPase and Na/Ca-exchanger (NCX). There is a concerted physiological coupling between these transporters. ( which means interdependence ) The function is an intracellular physiological role for the coordinated efforts of the Na+/K+-ATPase and NCX to actively remove Ca2+ from the nucleoplasm into the NE lumen (i.e. the nucleoplasmic reticulum). The Na+/K+-ATPase (Na pump) is an integral membrane protein that plays a central role in ionic homeostasis in animals by mediating the translocation of Na+ and K+ ions against their electrochemical gradients across the membrane.
How intracellular Calcium signalling, gradient and its role as a universal intracellular regulator points to design
It seems likely that these displacements have major implications for the spatiotemporal organization of the genome. For example, the organized nucleoplasmic flows generated by the dipolar forces could contribute to gene regulation by facilitating the distribution of the transcription machinery in the cell nucleus through advective instead of diffusive transport.