Heterochromatin
Encyclopedia
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin. Both play a role in the expression of genes
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
, where constitutive heterochromatin can affect the genes near them (position-effect variegation
Position-effect variegation
Position-effect variegation is a variegation caused by the inactivation of a gene in some cells through its abnormal juxtaposition with heterochromatin....
) and where facultative heterochromatin is the result of genes that are silenced through a mechanism such as histone methylation
Histone methylation
Histone methylation is the modification of certain amino acids in a histone protein by the addition of one, two, or three methyl groups. In the cell nucleus, DNA is wound around histones...
or siRNA
Small interfering RNA
Small interfering RNA , sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA molecules, 20-25 nucleotides in length, that play a variety of roles in biology. The most notable role of siRNA is its involvement in the RNA interference pathway, where it...
through RNAi. Constitutive heterochromatin is usually repetitive and forms structural functions such as centromeres or telomeres, in addition to acting as an attractor for other gene-expression or repression signals. Facultative heterochromatin is not repetitive and although it shares the compact structure of constitutive heterochromatin, facultative heterochromatin can, under specific developmental or environmental signaling cues, lose its condensed structure and become transcriptionally active. Heterochromatin is often associated with the di and tri-methylation of H3K9.
Structure
ChromatinChromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
is found in two varieties: euchromatin
Euchromatin
Euchromatin is a lightly packed form of chromatin that is rich in gene concentration, and is often under active transcription. Unlike heterochromatin, it is found in both cells with nuclei and cells without nuclei...
and heterochromatin. Originally, the two forms were distinguished cytologically by how intensely they stained - the euchromatin is less intense, while heterochromatin stains intensely, indicating tighter packing. Heterochromatin is usually localized to the periphery of the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
.
Heterochromatin mainly consists of genetically inactive satellite sequences
Satellite DNA
Satellite DNA consists of very large arrays of tandemly repeating, non-coding DNA. Satellite DNA is the main component of functional centromeres, and form the main structural constituent of heterochromatin....
, and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all. Both centromere
Centromere
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment...
s and telomere
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
s are heterochromatic, as is the Barr body
Barr body
A Barr body is the inactive X chromosome in a female somatic cell, rendered inactive in a process called lyonization, in those species in which sex is determined by the presence of the Y or W chromosome rather than the diploidy of the X or Z...
of the second, inactivated X-chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
in a female.
Function
Heterochromatin has been associated with several functions, from gene regulation to the protection of the integrity of chromosomes; 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, triggering cell cycleCell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
arrest, DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
, or destruction of the DNA fragment such as by endonuclease
Endonuclease
Endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain, in contrast to exonucleases, which cleave phosphodiester bonds at the end of a polynucleotide chain. Typically, a restriction site will be a palindromic sequence four to six nucleotides long. Most...
s in bacteria.
Some regions of chromatin are very densely packed with fibers displaying a condition comparable to that of the chromosome at mitosis. Heterochromatin is generally clonally inherited; when a cell divides the two daughter cells will typically contain heterochromatin within the same regions of DNA, resulting in epigenetic 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 (in cis) at these boundary domains. This gives rise to different levels of expression from cell to cell,
which may be demonstrated by position-effect variegation
Position-effect variegation
Position-effect variegation is a variegation caused by the inactivation of a gene in some cells through its abnormal juxtaposition with heterochromatin....
. Insulator
Insulator (genetics)
An insulator is a genetic boundary element that plays two distinct roles in gene expression, either as an enhancer-blocking element, or more rarely as a barrier against condensed chromatin proteins spreading onto active chromatin...
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, and loci in two Saccharomyces
Saccharomyces
Saccharomyces is a genus in the kingdom of fungi that includes many species of yeast. Saccharomyces is from Greek σάκχαρ and μύκης and means sugar fungus. Many members of this genus are considered very important in food production. One example is Saccharomyces cerevisiae, which is used in making...
spp.).
Constitutive heterochromatin
All cells of a given species will package the same regions of DNA in constitutive heterochromatinConstitutive heterochromatin
Constitutive heterochromatin domains are sections of DNA that occur throughout the chromosomes of eukaryotes, but particularly at the centromeres and telomeres. They often consist of very highly condensed, repetitive DNA and are largely transcriptionally silent...
, and thus in all cells any genes contained within the constitutive heterochromatin will be poorly expressed
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
. For example, all human chromosomes 1
Chromosome 1 (human)
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 247 million nucleotide base pairs, which are the basic units of information for DNA...
, 9
Chromosome 9 (human)
125px|rightChromosome 9 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome, as they normally do with all chromosomes...
, 16
Chromosome 16 (human)
125px|rightChromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs and represents just under 3 % of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic...
, and the Y-chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres.
Facultative heterochromatin
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 poorly expressed) may be packaged in euchromatin in another cell (and the genes within no longer silenced). However, the formation of facultative heterochromatin is regulated, and is often associated with morphogenesisMorphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
or differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
. An example of facultative heterochromatin is X-chromosome inactivation
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
in female mammals: one X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
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 include the Polycomb-group proteins
Polycomb-group proteins
Polycomb-group proteins are a family of proteins first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place...
and non-coding genes such as Xist. The mechanism for such spreading is still a matter of controversy.
Yeast heterochromatin
Saccharomyces cerevisiaeSaccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
, or budding yeast, is a model eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
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
Schizosaccharomyces pombe
Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measure 3 to 4 micrometres in diameter and 7 to 14 micrometres in length...
) uses another mechanism for heterochromatin formation at its centromeres. Gene silencing at this location depends on components of the RNAi
RNAI
RNAI is a non-coding RNA that is an antisense repressor of the replication of some E. coli plasmids, including ColE1. Plasmid replication is usually initiated by RNAII, which acts as a primer by binding to its template DNA. The complementary RNAI binds RNAII prohibiting it from its initiation role...
pathway. Double-stranded RNA is believed to result in silencing of the region through a series of steps.
In the fission yeast Schizosaccharomyces pombe
Schizosaccharomyces pombe
Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measure 3 to 4 micrometres in diameter and 7 to 14 micrometres in length...
two RNAi complexes, the RNAi-induced transcriptional gene silencing (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 a siRNA
Sírna
Sírna Sáeglach , son of Dian mac Demal, son of Demal mac Rothechtaid, son of Rothechtaid mac Main, was, according to medieval Irish legend and historical tradition, a High King of Ireland...
-dependent manner on chromosomes, at the site of heterochromatin assembly. RNA polymerase II
RNA polymerase II
RNA polymerase II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase...
synthesizes a transcript that serves as a platform to recruit RITS, RDRC and possibly other complexes required for heterochromatin assembly. Both RNAi and an exosome-dependent RNA degradation process contribute to heterochromatic gene silencing. These mechanisms of Schizosaccharomyces pombe
Schizosaccharomyces pombe
Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measure 3 to 4 micrometres in diameter and 7 to 14 micrometres in length...
may occur in other eukaryotes. A large RNA structure called RevCen
RevCen
RevCen is a family of non-coding RNA found in Schizosaccharomyces. It is a megastructure containing several siRNA which use the RNAi pathway to regulate heterochromatin formation. The long RNA transcript forms a secondary structure with several stem-loops which are processed by dicer into siRNA...
has also been implicated in the production of siRNAs to mediate heterochromatin formation in some fission yeast.