The human genome contains over 3 billion base pairs or nucleotides. These nucleotides, which are arranged in a linear sequence along DNA (deoxyribonucleic acid), encode every protein and genetic trait in the human body. This information is contained in approximately 20,000 genes which, surprisingly, represent only a small fraction (about 1.5%) of the total DNA. The remainder is comprised of non-coding sequences. The integrity of the genetic sequence is essential for normal cell function and this is highlighted when genetic anomalies go undetected by intrinsic genetic repair mechanisms and give rise to dysfunctional proteins and various diseases states.
A series of processes must therefore take place that enable the cell to package DNA within the confines of the nucleus whilst retaining its ability to transcribe and duplicate the entire DNA sequence and maintain its integrity. This is achieved through an elaborate process of DNA condensation that sees DNA packaged into 46 chromosomes (or 23 chromosome pairs) in humans. The number of chromosomes varies from species to species; for example, there are 40 chromosomes (20 pairs) in mice, 8 chromosomes (4 pairs) in the common fruit fly and 10 chromosomes (5 pairs) in the Arabidopsis thaliana plant.
Chromosomes reach their highest level of condensation during cell division, or mitosis, where they will acquire a discrete 4-armed or 2-armed morphology that represents approximately 10,000-fold compaction. Although this heavily condensed mitotic form has become the most common way of depicting chromosomes, their structure is significantly different during the interphase. Compared to mitotic chromosomes, interphase chromosomes are less condensed and occupy the entire nuclear space, making them somewhat difficult to distinguish.
Like the formation of metaphase chromosomes, the compaction required to fit a full set of interphase chromosomes into the nucleus is achieved through a series of DNA folding, wrapping and bending events that are facilitated by histones, which are highly conserved basic nuclear proteins that enable DNA compaction by neutralizing DNA’s negative charge. Histones generally arrange as an octamer in complex with DNA to form the nucleosome. The combination of DNA and histone proteins that make up the nuclear content is often referred to as chromatin.
Traditionally, interphase chromatin is classified as either euchromatin or heterochromatin, depending on its level of compaction. Euchromatin has a less compact structure, and is often described as a 11 nm fiber that has the appearance of ‘beads on a string’ where the beads represent nucleosomes and the string represents DNA. In contrast, heterochromatin is more compact, and is often reported as being composed of a nucleosome array condensed into a 30 nm fiber. It should be noted, however, that the 30 nm fiber has never been visualized in vivo, and its existence is questionable.
With DNA encoding the genetic information of the cell, the condensation of this molecule is obviously more complicated than can be represented by simple 11 nm or 30 nm fiber models. The transcription machinery requires access to the genetic information throughout the cell cycle, while replication machinery will copy the DNA during S-phase. This added complexity is evident in key differences between euchromatin and heterochromatin, and also in the localization of chromatin within the nucleus.
The fact that intrinsic mechanisms exist in the condensation of DNA to control access for transcriptional or replication purposes is reflected in the presence of repetitive DNA elements such as satellite sequences, as well as transposable elements within heterochromatin, particularly in the highly condensed centromeres and telomeres. These regions, which are known as constitutive heterochromatin, remain condensed throughout the cell cycle and are not actively transcribed. Facultative heterochromatin, which can be unwound to form euchromatin, on the other hand, is more dynamic in nature and can form and change in response to cellular signals and gene activity . This region often contains genetic information that will be transcribed during the cell cycle.