Heterochromatin is a form of chromatin that is densely packed—as opposed to euchromatin, which is lightly packed—and is found in the nucleus of eukaryotic cells. Whereas euchromatin allows the DNA to be replicated and transcribed, heterochromatin is in such a condensed structure that it does not enable DNA and RNA polymerases to access the DNA, therefore preventing DNA replication and transcription. There are two main types of heterochromatin: constructive heterochromatin and facultative heterochromatin. Heterochromatin represents less than 10% of the human chromatin, with euchromatin accounting for most of it—over 90%.
Before we jump onto the structure of heterochromatin, let’s take a look at how DNA is packaged in eukaryotic cells.
The DNA in eukaryotes is assembled into chromatin, which are complexes made of DNA and proteins. The proteins that form chromatin are called histones, and they are arranged in a way that allows DNA to be wrapped around them. More specifically, the DNA (about 200 base pairs) is coiled around sets of eight histones (octamers) comprising two copies of each of the following: H2A, H2B, H3 and H4. These units made of histones and DNA coiled around them are called nucleosomes. Nucleosomes are in turn connected to one another through DNA strings, also known as linker DNA. In other words, chromatin is the assembly of nucleosomes (DNA and histones) connected by the DNA itself.
The most loosely packaged form of chromatin is called euchromatin, also known as beads-on-a-string because of the resemblance between this structure and beads (nucleosomes) held together by a string (DNA). Heterochromatin is a more tightly condensed version of euchromatin and is also known as 30-nm fiber because the diameter of this helically coiled heterochromatin measures 30 nm. In fact, while G-banding shows very faintly stained euchromatin due to its loose form, heterochromatin is easily seen because it is densely stained due to its denser packaging. Heterochromatin can also be further condensed into active chromosomes and even further into metaphase chromosomes.
From left to right, double-stranded helical DNA (first illustration) is coiled around histones, forming nucleosomes (second illustration), which constitute the euchromatin or beads-on-a-string structure (third illustration). Euchromatin is further condensed into heterochromatin or 30-nm fibers (fourth and fifth illustrations). The last four illustrations depict more tightly condensed DNA in the form of active and metaphase chromosomes.
Looking at the figure above, we can also appreciate why DNA is in the heterochromatin conformation when it is not being actively replicated or transcribed: the DNA is not exposed and therefore regulatory proteins and polymerases cannot access it. Note the difference between euchromatin (third illustration) and heterochromatin (fourth and fifth): while linker DNA in the euchromatic conformation is exposed and accessible to polymerases and other proteins in order to be replicated and transcribed, the DNA in the heterochromatic conformation is tightly coiled around the nucleosomes and does not allow access to transcriptional elements.
The Two Types of Heterochromatin: Constitutive and Facultative
The structure of heterochromatin can be described in more detail by taking into account its several types. The two main types are constitutive heterochromatin and facultative heterochromatin. These two types can be distinguished based on their features. It has been suggested that other types of heterochromatin also exist and that these other types have mixed features of constitutive and facultative heterochromatin.
Constitutive heterochromatin is the stable form of heterochromatin, i.e. it does not loosen up to form euchromatin, and contains repeated sequences of DNA called satellite DNA. It can be found in centromeres and telomeres, and is usually involved in structural functions.
Facultative heterochromatin, on the other hand, is reversible, i.e. its structure can change depending on the cell cycle, and is characterized by another kind of repeated DNA sequence known as LINE sequences. An example of facultative heterochromatin that changes its structural conformation with the cell cycle is the inactivated X-chromosome (Barr body) of females.
The Cell Cycle and Gene Expression
It is not surprising that the way in which the DNA is packaged is related to the cell cycle. When the DNA needs to be copied (replicated) and proteins need to be synthesized (transcription and then translation), the DNA is found in the euchromatin form. When genes do not need to be replicated and transcribed, the DNA is in the heterochromatin form. Furthermore, when the DNA is in the active chromosome form, the cell is in the interphase stage of the cell cycle, and when it is in the metaphase chromosome form, the cell is in dividing, i.e. it is in the mitosis or meiosis stage.
In line with this, it has been proposed that regulating the way in which the DNA is packaged is a way of regulating gene expression. Therefore, housekeeping genes that maintain the functions and survival of the cell are always in the euchromatin form, whereas those that do not need to be expressed are in the heterochromatin form. The means by which this is achieved is by modification of the histone tail, a part of the histones that can be acetylated or methylated. Modifying the histone tail results in changes in the packaging of the DNA. For instance, hypoacetylation on the histone tail is associated with the heterochromatic conformation, whereby DNA is not exposed and consequently gene transcription is prevented.