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Heterochromatin, from Chromosome to Protein

Marie-Geneviève Mattei and Judith Luciani


INSERM U 491, Faculté de Médecine, Bd Jean Moulin, 13385 Marseille, France
(Paper co-edited with E.C.A. Newsletter)

January 2003

 

 

I THE CONCEPT OF HETEROCHROMATIN

Definition of Chromatin
In prokaryotes such as Escherichia coli there is no detectable heterochromatin, for the simple reason that there is no chromatin. The hereditary message is carried by a circular molecule of naked DNA, and there is no separate nuclear compartment.
In eukaryotes, however, the DNA is packaged in the form of a nucleoprotein complex called "chromatin". The hereditary message is, therefore, carried by the chromatin. It is located in a nucleus and is organised in several separate entities, the chromosomes.

The Concept of Heterochromatin
The concept of heterochromatin, as described by Emil HEITZ in 1928, was exclusively based on histological observations. He defined heterochromatin (HC) as being the chromosomal segments which appear extremely condensed and dark in colour in the interphase nucleus. The rest of the nucleus is occupied by euchromatin, or true chromatin, which appears diffuse and relatively light in colour. Heitz's observations highlighted the fact that, in the interphase nucleus, chromatin does not have a homogeneous appearance. Electron microscopy and X-ray diffraction have since confirmed the heterogeneous structure of chromatin: it consists of a tangle of fibres, the diameter of which not only vary during the cell cycle, but also depend on the region of the chromosome observed. Euchromatin, in its active form, consists of a fibre with a diameter not exceeding 10-11nm. Its diameter corresponds to that of a nucleosome, which contains a 146 base pair double strand DNA segment, wound around 4 homodimers of the histones H2A, H2B, H3, and H4 .
The inactive euchromatin is enriched in linker histone H1. Histone H1 binds two consecutive nucleosomes, which causes the 10-11nm fibre to wind itself into a solenoid with a 30nm diameter. The 30nm fibre is further organised through interactions with non-histone proteins which fold the chromatin fibre in loops around an imaginary axis. These proteins include topoisomerase II, which is located, in particular, at the base of the loops, the scaffold protein 2 and lamins, in addition to other proteins. At this stage, the diameter of the chromatin fibre attains approximately 200nm. As regards the heterochromatin, as defined above, its constituent fibre is more condensed and often appears to be composed of aggregates. It involves numerous additional proteins, including the HP1 proteins (Heterochromatin Protein 1).

 

II TWO TYPES OF HETEROCHROMATIN

There are two types of heterochromatin, constitutive HC and facultative HC, which differ slightly, depending on the DNA that they contain. The richness in satellite DNA determines the permanent or reversible nature of the heterochromatin, its polymorphism and its staining properties (Table I).

Table I: Properties which allow to differentiate constitutive from facultative heterochromatin.

Table I: Properties which allow to differentiate constitutive from facultative heterochromatin.

1) Richness in satellite DNA
 
2) Stability:

 

3) Polymorphism

 

4) C-band Staining :

 

III PROPERTIES OF HETEROCHROMATIN

Despite the differences described above, constitutive HC and facultative HC have very similar properties.

1) Heterochromatin is condensed
This is in fact what defines heterochromatin, and it is applicable to both constitutive HC and facultative HC. This high condensation renders it strongly chromophilic, and the intensity of HC staining is directly proportional to its degree of condensation.
The strongly condensed nature of heterochromatin has another consequence, in that it renders it inaccessible to DNAse 1 and to other restriction enzymes in general.

 

2) Heterochromatin DNA is late replicating

The incorporation of various nucleotide analogues shows that the DNA from both constitutive and facultative HC, is late replicating.
The DNA of the inactive X is very late replicating, as it replicates at the end of the late S phase. The incorporation of 5-Bromodeoxyuridine four hours before harvesting allows this to be clearly seen.
As regards the heterochromatic centromere regions, their replication precedes that of the inactive X and takes place at the beginning of the late S phase. The centromeric DNA must, therefore, replicate sufficiently early to allow the formation, with the centromeric proteins, of a nuclear-protein complex that will be functional during mitosis.

 
3) Heterochromatin DNA is methylated

The DNA of constitutive HC is highly methylated, with the methylation occurring exclusively on the cytosines. An anti-5-methyl cytosine antibody therefore strongly labels all the regions of constitutive HC, thus showing both its richness in cytosines and their methylation.
As regards facultative HC, the methylation of the DNA is more discrete, and cannot be detected using an antibody directed against methylated cytosines. Nevertheless, restriction enzymes that are sensitive to methylation can be used to reveal strong methylation of the CpG islands, which are specifically located in the control regions of the genes.

 

4) In heterochromatin, histones are hypo-acetylated:

Histones may undergo post-translational modifications of their N-terminal ends which may affect the genetic activity of the chromatin.
It has long been known that the hypo-acetylation of histone N-terminal tails is a modification that is associated with an inactive chromatin. In contrast, however, hyper-acetylated histones characterise the active chromatin. It is principally the lysines ("K" in single-letter code language) of the histones that are acetylated.
Acetylation/de-acetylation of histones is a mechanism that is absolutely essential for the control of gene expression. Numerous transcription factors have been shown to have, either an activity Histone Acétyl Transférase (HAT) in the case of co-activators, or Histone De-ACétylases (HDAC) in the case of co-repressors.

 

5) Histones from heterochromatin are methylated on lysine 9:
This modification of the N-terminal tail of histones has only very recently been discovered and found to be involved in the process of heterochromatinisation of the genome. It characterises both constitutive HC and facultative HC.
Methylation of the H3 histone occurs on a very specific residue, lysine 9, hence its name, H3-K9. The H3-K9 lysine may be mono-methylated, di-methylated or tri-methylated, and a high degree of methylation promotes the binding of the HP1 (Heterochromatin Protein 1) proteins.
 

6) Heterochromatin is transcriptionally inactive:

Incorporating tritiated uridine into a cell culture does not result in any labelling of the heterochromatin. Human constitutive HC does not contain any genes, which explains why transcription does not take place at these sites. In Drosophila, on the other hand, certain genes, such as the rolled and light genes, are usually located in and expressed from the constitutive HC. The facultative HC is relatively poor in genes, and its genes are not usually transcribed in a heterochromatic context.

 

7) Heterochromatin does not participate in genetic recombination:
It is generally accepted that constitutive HC does not participate in genetic recombination. The reason for this is that there is no preliminary pairing of the homologous heterochromatic regions, even though some aggregation of these regions is often observed. In any case, the polymorphism that characterises the heterochromatic regions would render such pairing difficult, if not impossible. Moreover, this is the reason why the pericentric inversion of the secondary constriction of chromosome 9 has no effect in terms of chromosome mechanics and can be considered as a normal variant.
Not only does the constitutive HC not participate in recombination, it also acts to repress recombination in adjacent euchromatic regions.
As regards the facultative HC, it does not participate in meiotic recombination when it is in its inactive form.

 

8) Heterochromatin has a gregarious instinct:

The study of various organisms has shown that constitutive HC has a genuine tendency to aggregate during interphase.

Thus, in the interphase nuclei of the salivar glands of Drosophila larvae, the centromeres of polytene chromosomes, which are rich in heterochromatin, aggregate to form the chromocentres.

In the mouse, the number of heterochromatic blocks that can be observed in interphase nuclei is always lower than the number of heterochromatic regions visualised on the metaphase chromosomes. The relationship between the size and the number of HC blocks in interphase suggests a coalescence of the heterochromatic regions.

In the human, the short arms of the acrocentric chromosomes, which are mainly formed from heterochromatin, carry the nucleolar organiser regions. They are frequently associated in the interphase nucleus, and this does not appear to result solely from their common function. Indeed, numerous other chromosomes are involved in this association, and the participation of each of them is all the more marked because it carries a large HC block, as is the case for chromosomes 1, 9 or 16.

This tendency of the heterochromatin to aggregate appears to be strongly linked to the presence of satellite DNA sequences, but this is a property which may not be exclusive and may involve other additional sequences.

 

IV FACTEURS INVOLVED in HETEROCHROMATINISATION

There are probably various diverse ways of organising a genomic region into heterochromatin. Certain observations have, however, led to the identification of various elements that have an important role in the formation of heterochromatin, be it constitutive or facultative.

 

1) Large arrays of tandemly repeated sequences.

The fact that in the human genome, as well as in the genome of other organisms, the localisation of the satellite DNA visualised by FISH corresponds exactly to that of the constitutive heterochromatin stained by DAPI, highlights the potential role of satellite DNA in the formation of this type of heterochromatin. Indeed, this type of DNA sequence has the distinctive feature of bending and folding upon itself, and this may be an important factor in determining the extremely compact structure of the constitutive DNA.
However, this does not only concern satellite DNA. In plants, Drosophila, and also in the mouse, certain multicopy transgenes are barely expressed, or are not expressed at all, even when they are not subject to centromere repression.

These different observations suggest that the tandem repetition of a DNA sequence in a large number of copies is sufficient on its own to direct the formation of heterochromatin. The presence of repetitive DNA, such as satellite DNA, appears to simply allow the chromatin to be compacted to a greater extent, as is the case for constitutive heterochromatin. The mechanism would appear to be as follows: the large arrays of tandemly repeated DNA sequences appear to be able to pair, thus forming characteristic structures. These structures would then appear to be recognised by specific proteins, such as the HP1 proteins, which in turn direct the formation of a higher-order chromatin.

 

2) Methylation of DNA

Although the presence of tandemly repeated sequences is important, it is not the only factor, as large repetitions of transgenes do not all lead to a transcriptional inactivation of the transgene. Most often, the silencing induced by the tandem repeats appears to be linked to the presence of prokaryotic DNA sequences that are rich in CpG and, therefore, likely to be methylated (for example, the lacZ gene). The base composition of the tandem repeat and, in particular, its ability to be methylated could therefore play an important role in the formation of heterochromatin.
Interestingly, it has recently been shown that there is a direct relationship between the methylation of DNA and the de-acetylation of histones, both of which characterise heterochromatic structures. The methyl binding protein MeCP2, which normally binds to DNA containing methylated cytosines, has thus been shown to be able to recruit histone de-acetylases (Figure 1). Methylation of the DNA could therefore induce a de-acetylation of histones and thus promote heterochromatisation.

Figure 1: DNA methylation induces Histone de-acetylation, modification which characterizes histones in both heterochromatin and repressed euchromatin.
MeCP2 specifically binds to methylated DNA, and recruits an HDAC which de-acetylates histones (Ac= Acetyl; Me= Methyl; MeCP2= Methyl-CpG binding Protein 2; HDAC= Histone De-Acetylase).

However, the methylation of DNA is not indispensable for the formation of heterochromatin. It could be an element involved in stabilisation, as has been shown for the facultative HC of the inactive X. Indeed, in marsupials, the inactive X is not methylated and is much less stable than in eutherian mammals.

 

3) Regular organisation of nucleosomes
We have seen that sequences of prokaryotic DNA inserted into eukaryotes have the ability to be methylated and can induce the formation of heterochromatin. Heterochromatisation may not, however, depend solely on the methylation of the CpGs contained in the DNA.
A study of the chromatin of different transgenes digested by a micrococcal nuclease provided interesting results. The chromatin of a transgene inserted into constitutive HC revealed a very regular organisation of the nucleosome that was much more regular than the organisation revealed by the same transgene inserted into an euchromatic region. It appears that this regularity of the structure is able either to take on a particular conformation or to be recognised by specific proteins, and, in this way, can promote the formation of heterochromatic structures.

 

4) Hypo-acetylation of Histones

We have seen that hypo-acetylation of histones is a characteristic of silent chromatin, whether it is heterochromatin or not. In vitro, the modification of the acetylation of the histones has a direct effect on the stability and compaction of the nucleosomes. Thus, blocking the de-acetylation of the histones by adding trichostatine A induces hyper-acetylation of the histones, which causes a more open chromatin structure.

The mechanism involved is simple: in the N-terminal tail of the histones, the basic amino-acids such as lysine are positively-charged at cellular pH and therefore interact with the negative charges of the DNA phosphates.

Hypo-acetylation of the histones is not the only modification of the N-terminal tails of the histones that characterises heterochromatin. Three other modifications have been shown to be more specifically linked to silencing: the phosphorylation of serine 10 of histone H3, the acetylation of lysine 12 of histone H4 and the methylation of lysine 9 of histone H3 (H3-K9). We will present the last of these modifications in more detail.

 

5) Methylation of H3-K9

Methylation of the histone H3 on lysine 9 is an epigenetic modification of histones that has recently been shown to be involved in the process of heterochromatinisation. This has been demonstrated not only in constitutive HC but also on the inactive X. The enzyme responsible for the methylation of H3-K9 in constitutive HC is the histone methyltransferase SUV39H1.

Figure 2: Histone H3-K9 methylation induces DNA methylation, modification which characterizes DNA in heterochromatin and repressive euchromatin.
SUVAR39H is a methyltransferase which specifically methylates the Lysine 9 of histone H3. Such a methylation creates a binding site for the Heterochromatin Protein HP1 which recruits a DNA methyl transferase, capable to methylate the CpG in DNA (Me= Methyl; Methyl H3-K9= Methyl on Lysin 9 of Histone H3; HP1=Heterochromatin Protein 1; DNMT=DNA Methyl transferase).

 

6) HP1 proteins

Many different heterochromatin proteins are to be found in mammals, and at the present time little is known about them. The HP1 proteins do appear, however, to have a particular role in the organisation of heterochromatin. Studies of the variegation by position effect (PEV effect) in Drosophila and studies of transgenes in Drosophila and mouse have allowed a better understanding of the role of HP1 proteins.

In all cases, HP1 proteins or their homologues appear to be an essential link in the formation of heterochromatin. These heterochromatin-specific proteins could have the role of chromatin domain organisers. The HP1 proteins thus appear to be able to recognise particular structures that are created by the pairing and/or the association of repeated DNA sequences. In addition, they appear to be able to establish secondary interactions with a large number of other proteins. The HP1 proteins are perfectly adapted for such interactions, as they have two domains of protein/protein interaction, the chromodomain (CD) and the chromoshadow domain (CSD).

 

7) Nuclear RNAs

It is already well established that certain nuclear RNAs are able to contribute to the formation of facultative HC. The transcripts of the XIST (X inactive Specific Transcripts) gene are nuclear RNAs that have an essential role in the facultative inactivation of one X chromosome, which occurs in the somatic cells in female mammals. This XIST RNA is necessary for the initiation of X inactivation, but not its maintenance. Other nuclear RNAs, such as H19, have been shown to be involved in the regulation of genes that are subject to genomic imprinting.

Some recent studies in mouse have suggested that nuclear transcripts may also be involved in the formation of constitutive HC. In mouse, as in most other species, the centromeric HC is particularly stable. It is characterised by the presence of a high concentration of methylated H3-K9 histone and heterochromatic HP1 proteins, which co-localise in the nuclei with regions strongly stained with DAPI. However, incubation of permeabilised mouse cells with RNAse A causes rapid de-localisation of the HP1 and methylated H3-K9 signals, in relation to the heterochromatin foci. These data suggest that a nuclear RNA may be an essential structural component of constitutive HC. The RNA may either facilitate compaction of the centromeric HC or may serve as an additional binding site for the proteins that associate with the chromatin. Surprisingly, the treatment with RNAse A does not alter the methylated H3-K9 signals at the level of the Barr body. In fact, on the inactive X chromosome, the methylation of H3-K9 does not appear to lead to the binding of HP1 proteins. This suggests that the facultative heterochromatinisation of the inactive X may require a different mechanism to come into play from that of constitutive HC.

 

V FUNCTIONS OF HETEROCHROMATIN

The precise role of heterochromatin in the human genome long remained a mystery, as its frequent polymorphisms did not appear to have any functional or phenotypic effect.

 

1) Role of HC in the organisation of nuclear domains

 

2) Role of HC in the centromeric function

In most eukaryotes, the centromeres are loaded with a considerable mass of heterochromatin. It has been suggested that centromeric HC is necessary for the cohesion of sister chromatids and that it allows the normal disjunction of mitotic chromosomes.

 

3) Does centromeric HC act as a transporter?
Many proteins have been shown to be associated with centromeric HC, in particular on metaphase chromosomes. It can be assumed that certain proteins that must be present and functional at the very beginning of the G1 phase will not be able to be synthesised due to a lack of time. Following this hypothesis, binding to the centromere would be an ideal means for such proteins to traverse cell division unhindered, in order to be available at the beginning of G1.


4) Role of HC in gene repression (epigenetic regulation)
Gene expression may be controlled at two levels:
Heterochromatin appears to be involved in controlling the transcriptability of the genome. Genes that are usually located in the euchromatin can, therefore, be silenced when they are placed close to a heterochromatic domain.

 

  VI HETEROCHROMATIN DISEASES

1) Diseases of the constitutive heterochromatin

These diseases are generally the result of an alteration in the process of cell differentiation.

 

2) Diseases of the facultative heterochromatin

 

VII CONCLUSION

In conclusion, although heterochromatin is apparently amorphous and isolated at the periphery of the nucleus, it appears to have an absolutely essential role in the organisation and function of the genome.
Throughout this review we have mainly presented the characteristics linked with heterochromatin, be it constitutive or facultative. We have shown that the properties of constitutive HC, despite the presence of satellite DNA, are not fundamentally different from those of facultative HC. It therefore seems clear that the mechanisms involved in facultative heterochromatinisation, which are epigenetic mechanisms, are the same mechanisms that intervene in the repression of euchromatin in general.

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Contributor(s)

Written01-2003Marie-Geneviève Mattei and Judith Luciani
Inserm U 491, faculte de medecine, boulevard jean moulin, 13385 marseille, France

Citation

This paper should be referenced as such :
Mattei MG, Luciani J
Heterochromatin, from Chromosome to Protein
Atlas Genet Cytogenet Oncol Haematol. January 2003
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