Heterochromatin is a tightly packed form ofDNA orcondensed DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes ofconstitutive heterochromatin andfacultative heterochromatin. Both play a role in theexpression of genes. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002),[1] and many other papers since,[2] much of this DNA is in fact transcribed, but it is continuouslyturned over viaRNA-induced transcriptional silencing (RITS). Recent studies withelectron microscopy andOsO4 staining reveal that the dense packing is not due to the chromatin.[3]
Constitutive heterochromatin can affect the genes near itself (e.g.position-effect variegation). It is usuallyrepetitive and forms structural functions such ascentromeres ortelomeres, in addition to acting as an attractor for other gene-expression or repression signals.
Facultative heterochromatin is the result of genes that aresilenced through a mechanism such ashistone deacetylation orPiwi-interacting RNA (piRNA) throughRNAi. It is not repetitive and shares the compact structure of constitutive heterochromatin. However, under specific developmental or environmental signaling cues, it can lose its condensed structure and become transcriptionally active.[4]
Heterochromatin has been associated with thedi- andtri -methylation ofH3K9 in certain portions of the human genome.[5]H3K9me3-relatedmethyltransferases appear to have a pivotal role in modifying heterochromatin during lineage commitment at the onset oforganogenesis and in maintaining lineage fidelity.[6]
Chromatin is found in two varieties:euchromatin and heterochromatin.[7] Originally, the two forms were distinguished cytologically by how intensely they get stained – the euchromatin is less intense, while heterochromatin stains intensely, indicating tighter packing. Heterochromatin was given its name for this reason by botanist Emil Heitz who discovered that heterochromatin remained darkly stained throughout the entire cell cycle, unlike euchromatin whose stain disappeared during interphase.[8] Heterochromatin is usually localized to the periphery of thenucleus.Despite this early dichotomy, recent evidence in both animals[9] and plants[10] has suggested that there are more than two distinct heterochromatin states, and it may in fact exist in four or five 'states', each marked by different combinations ofepigenetic marks.
Heterochromatin mainly consists of genetically inactivesatellite sequences,[11] and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all.[12] Bothcentromeres andtelomeres are heterochromatic, as is theBarr body of the second, inactivatedX-chromosome in a female.
Heterochromatin has been associated with several functions, from gene regulation to the protection of chromosome integrity;[13] some of these roles can be attributed to the dense packing of DNA, which makes it less accessible to protein factors that usually bind DNA or its associated factors. For example, naked double-stranded DNA ends would usually be interpreted by the cell as damaged or viral DNA, triggeringcell cycle arrest,DNA repair or destruction of the fragment, such as byendonucleases in bacteria.
Some regions of chromatin are very densely packed with fibers that display a condition comparable to that of the chromosome atmitosis. Heterochromatin is generally clonally inherited; when a cell divides, the two daughter cells typically contain heterochromatin within the same regions of DNA, resulting inepigenetic inheritance. Variations cause heterochromatin to encroach on adjacent genes or recede from genes at the extremes of domains. Transcribable material may be repressed by being positioned (incis) at these boundary domains. This gives rise to expression levels that vary from cell to cell,[14] which may be demonstrated byposition-effect variegation.[15]Insulator sequences may act as a barrier in rare cases where constitutive heterochromatin and highly active genes are juxtaposed (e.g. the 5'HS4 insulator upstream of the chicken β-globin locus,[16] and loci in twoSaccharomyces spp.[17][18]).
All cells of a given species package the same regions of DNA inconstitutive heterochromatin, and thus in all cells, any genes contained within the constitutive heterochromatin will be poorlyexpressed. For example, all human chromosomes1,9,16, and theY-chromosome contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres.
The regions of DNA packaged in facultative heterochromatin will not be consistent between the cell types within a species, and thus a sequence in one cell that is packaged in facultative heterochromatin (and the genes within are poorly expressed) may be packaged in euchromatin in another cell (and the genes within are no longer silenced). However, the formation of facultative heterochromatin is regulated, and is often associated withmorphogenesis ordifferentiation. An example of facultative heterochromatin isX chromosome inactivation in female mammals: oneX chromosome is packaged as facultative heterochromatin and silenced, while the other X chromosome is packaged as euchromatin and expressed.
Among the molecular components that appear to regulate the spreading of heterochromatin are thePolycomb-group proteins and non-coding genes such asXist. The mechanism for such spreading is still a matter of controversy.[19] The polycomb repressive complexesPRC1 andPRC2 regulatechromatin compaction and gene expression and have a fundamental role in developmental processes. PRC-mediatedepigenetic aberrations are linked togenome instability and malignancy and play a role in theDNA damage response,DNA repair and in the fidelity ofreplication.[20]
Saccharomyces cerevisiae, or budding yeast, is a modeleukaryote and its heterochromatin has been defined thoroughly. Although most of its genome can be characterized as euchromatin,S. cerevisiae has regions of DNA that are transcribed very poorly. These loci are the so-called silent mating type loci (HML and HMR), the rDNA (encoding ribosomal RNA), and the sub-telomeric regions.Fission yeast (Schizosaccharomyces pombe) uses another mechanism for heterochromatin formation at its centromeres. Gene silencing at this location depends on components of theRNAi pathway. Double-stranded RNA is believed to result in silencing of the region through a series of steps.
In the fission yeastSchizosaccharomyces pombe, two RNAi complexes, the RITS complex and the RNA-directed RNA polymerase complex (RDRC), are part of an RNAi machinery involved in the initiation, propagation and maintenance of heterochromatin assembly. These two complexes localize in asiRNA-dependent manner on chromosomes, at the site of heterochromatin assembly.RNA polymerase II synthesizes a transcript that serves as a platform to recruit RITS, RDRC and possibly other complexes required for heterochromatin assembly.[21][22] Both RNAi and an exosome-dependent RNA degradation process contribute to heterochromatic gene silencing. These mechanisms ofSchizosaccharomyces pombe may occur in other eukaryotes.[23] A large RNA structure calledRevCen has also been implicated in the production of siRNAs to mediate heterochromatin formation in some fission yeast.[24]
An up-to-date account of the current understanding of repetitive DNA, which usually doesn't contain genetic information. If evolution makes sense only in the context of the regulatory control of genes, we propose that heterochromatin, which is the main form of chromatin in higher eukaryotes, is positioned to be a deeply effective target for evolutionary change. Future investigations into assembly, maintenance and the many other functions of heterochromatin will shed light on the processes of gene and chromosome regulation.
