Position-effect variegation

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Position-effect variegation (PEV) is a variegation caused by the silencing of a gene in some cells through its abnormal juxtaposition with heterochromatin via rearrangement or transposition. [1] It is also associated with changes in chromatin conformation. [2]

Contents

Overview

The classical example is the Drosophila wm4 (speak white-mottled-4) translocation. In this mutation, an inversion on the X chromosome placed the white gene next to pericentric heterochromatin, or a sequence of repeats that becomes heterochromatic. [3] Normally, the white gene is expressed in every cell of the adult Drosophila eye resulting in a red-eye phenotype. In the w[m4] mutant, the eye color was variegated (red-white mosaic colored) where the white gene was expressed in some cells in the eyes and not in others. The mutation was described first by Hermann Muller in 1930. [4] PEV is a heterochromatin-induced gene inactivation. [5] Gene silencing phenomena similar to this have also been observed in S. cerevisiae and  S. pombe. [5]

Typically, the barrier DNA sequences prevent the heterochromatic region from spreading into the euchromatin but they are no longer present in the flies that inherit certain chromosomal rearrangements. [6]

Etymology

PEV is a position effect because the change in position of a gene from its original position to somewhere near a heterochromatic region has an effect on its expression. [7] The effect is the variegation in a particular phenotype i.e., the appearance of irregular patches of different colour(s), due to the expression of the original wild-type gene in some cells of the tissue but not in others, [8] as seen in the eye of mutated Drosophila melanogaster.

However, it is possible that the effect of the silenced gene is not phenotypically visible in some cases. PEV was observed first in Drosophila because it was one of the first organisms on which X-ray irradiation was used as a mutation inducer. [1] X-rays can cause chromosomal rearrangements that can result in PEV. [1]

Mechanisms

Among a number of models, two epigenetic models are popular. One is the cis-spreading of the heterochromatin past the rearrangement breakpoint. The trans-interactions come in when the cis-spreading model is unable to explain certain phenomena. [5]

cis-spreading

According to this model, the heterochromatin forces an altered chromatin conformation on the euchromatic region. Due to this, the transcriptional machinery cannot access the gene which leads to the inhibition of transcription. [5] In other words, the heterochromatin spreads and causes gene silencing by packaging the normally euchromatic region. [2] But this model fails to explain some aspects of PEV. For example, variegation can be induced in a gene located several megabases from the heterochromatin-euchromatin breakpoint due to rearrangements in that breakpoint. Also, the austerity of the variegated phenotype can be altered by the distance of the heterochromatic region from the breakpoint. [5]

This suggests that trans-interactions are crucial for PEV.

trans-interactions 

These are interactions between the different heterochromatic regions and the global chromosomal organisation in the interphase nucleus. [5] The rearrangements due to PEV places the reporter gene in a new compartment of the nucleus where the transcriptional machinery required is not available, thus silencing the gene and modifying the chromatin structure. [2]

These two mechanisms affect each other as well. Which mechanism dominates to influence the phenotype depends upon the type of heterochromatin and the intricacy of the rearrangement. [5]

Suppression in Drosophila melanogaster

The mutations in mus genes are the candidates as PEV modifiers, as these genes are involved in chromosome maintenance and repair. Chromosome structure in the vicinity of the breakpoint appears to be an important determinant of the gene inactivation process. Six second chromosomal mus mutations were isolated with wm4. A copy of wild-type white gene was placed adjacent to heterochromatin. The different mus mutants that were taken were: mus201D1, mus205B1, mus208B1, mus209B1, mus210B1, mus211B1. A stock was constructed with the replacement of standard X-chromosome with wm4. It was observed that the suppression of PEV is not a characteristic of mus mutations in general. Only for homozygous mus209B1, the variegation was significantly suppressed. Also, when homozygous, 2735 and D-1368 and all heteroallelic combinations of its Pcna mutations strongly suppress PEV. [9]

In other organisms

In mouse

In mouse, variegating coat colour has been observed. When an autosomal region carrying a fur color gene is inserted onto the X chromosome, variable silencing of the allele is seen. Variegation is, however, observed only in the female having this insertion along with a homozygous mutation in the original coat color gene. [1] The wild-type allele gets inactivated due to heterochromatinization. [1]

In plants

In plants, PEV has been observed in Oenothera blandina. The silencing of euchromatic genes occurs when the genes get placed into a new heterochromatic neighborhood. [1]

See also

Related Research Articles

Centromere Specialized DNA sequence of a chromosome that links a pair of sister chromatids

The centromere is the specialized DNA sequence of a chromosome that links a pair of sister chromatids. During mitosis, spindle fibers attach to the centromere via the kinetochore. Centromeres were first thought to be genetic loci that direct the behavior of chromosomes.

Heterochromatin is a tightly packed form of DNA or condensed DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role in the expression 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), and many other papers since, much of this DNA is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO4 staining reveal that the dense packing is not due to the chromatin.

Mosaic (genetics)

Mosaicism or genetic mosaicism is a condition in multi-cellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized egg. Genetic mosaics may often be confused with chimerism, in which two or more genotypes arise in one individual similarly to mosaicism. In chimerism, though, the two genotypes arise from the fusion of more than one fertilized zygote in the early stages of embryonic development, rather than from a mutation or chromosome loss.

Constitutive heterochromatin

Constitutive heterochromatin domains are regions of DNA found throughout the chromosomes of eukaryotes. The majority of constitutive heterochromatin is found at the pericentromeric regions of chromosomes, but is also found at the telomeres and throughout the chromosomes. In humans there is significantly more constitutive heterochromatin found on chromosomes 1, 9, 16, 19 and Y. Constitutive heterochromatin is composed mainly of high copy number tandem repeats known as satellite repeats, minisatellite and microsatellite repeats, and transposon repeats. In humans these regions account for about 200Mb or 6.5% of the total human genome, but their repeat composition makes them difficult to sequence, so only small regions have been sequenced.

Position effect is the effect on the expression of a gene when its location in a chromosome is changed, often by translocation. This has been well described in Drosophila with respect to eye color and is known as position effect variegation (PEV).

Transvection is an epigenetic phenomenon that results from an interaction between an allele on one chromosome and the corresponding allele on the homologous chromosome. Transvection can lead to either gene activation or repression. It can also occur between nonallelic regions of the genome as well as regions of the genome that are not transcribed.

An insulator is a type of cis-regulatory element known as a long-range regulatory element. Found in multicellular eukaryotes and working over distances from the promoter element of the target gene, an insulator is typically 300 bp to 2000 bp in length. Insulators contain clustered binding sites for sequence specific DNA-binding proteins and mediate intra- and inter-chromosomal interactions.

Polycomb-group proteins are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes through modulation of chromatin structure during embryonic development in fruit flies. They derive their name from the fact that the first sign of a decrease in PcG function is often a homeotic transformation of posterior legs towards anterior legs, which have a characteristic comb-like set of bristles.

The family of heterochromatin protein 1 (HP1) consists of highly conserved proteins, which have important functions in the cell nucleus. These functions include gene repression by heterochromatin formation, transcriptional activation, regulation of binding of cohesion complexes to centromeres, sequestration of genes to nuclear periphery, transcriptional arrest, maintenance of heterochromatin integrity, gene repression at the single nucleosome level, gene repression by heterochromatization of euchromatin and DNA repair. HP1 proteins are fundamental units of heterochromatin packaging that are enriched at the centromeres and telomeres of nearly all Eukaryotic chromosomes with the notable exception of budding yeast, in which a yeast-specific silencing complex of SIR proteins serve a similar function. Members of the HP1 family are characterized by an N-terminal chromodomain and a C-terminal chromoshadow domain, separated by a Hinge region. HP1 is also found at euchromatic sites, where its binding correlates with gene repression. HP1 was originally discovered by Tharappel C James and Sarah Elgin in 1986 as a factor in the phenomenon known as position effect variegation in Drosophila melanogaster.

RNA-induced transcriptional silencing (RITS) is a form of RNA interference by which short RNA molecules – such as small interfering RNA (siRNA) – trigger the downregulation of transcription of a particular gene or genomic region. This is usually accomplished by posttranslational modification of histone tails which target the genomic region for heterochromatin formation. The protein complex that binds to siRNAs and interacts with the methylated lysine 9 residue of histones H3 is the RITS complex.

CBX1

Chromobox protein homolog 1 is a protein that in humans is encoded by the CBX1 gene.

CBX3

Chromobox protein homolog 3 is a protein that is encoded by the CBX3 gene in humans.

EZH2

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

SUV39H1

Histone-lysine N-methyltransferase SUV39H1 is an enzyme that in humans is encoded by the SUV39H1 gene.

ATRX

Transcriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein (XNP) is a protein that in humans is encoded by the ATRX gene.

CBX5 (gene)

Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene. It is a highly conserved, non-histone protein part of the heterochromatin family. The protein itself is more commonly called HP1α. Heterochromatin protein-1 (HP1) has an N-terminal domain that acts on methylated lysines residues leading to epigenetic repression. The C-terminal of this protein has a chromo shadow-domain (CSD) that is responsible for homodimerizing, as well as interacting with a variety of chromatin-associated, non-histone proteins.

Sarah Elgin American biologist

Sarah C.R. Elgin is an American biochemist and geneticist. She is the Viktor Hamburger Professor of biology at Washington University in St. Louis, and is noted for her work in epigenetics, gene regulation, and heterochromatin, and for her contributions to science education.

SilentInformationRegulator (SIR) proteins are involved in regulating gene expression. SIR proteins organize heterochromatin near telomeres, rDNA, and at silent loci including hidden mating type loci in yeast. The SIR family of genes encodes catalytic and non-catalytic proteins that are involved in de-acetylation of histone tails and the subsequent condensation of chromatin around a SIR protein scaffold. Some SIR family members are conserved from yeast to humans.

Robin Campbell Allshire is Professor of Chromosome Biology at University of Edinburgh and a Wellcome Trust Principal Research Fellow. His research group at the Wellcome Trust Centre for Cell Biology focuses on the epigenetic mechanisms governing the assembly of specialised domains of chromatin and their transmission through cell division.

Thomas Jenuwein

Thomas Jenuwein is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.

References

  1. 1 2 3 4 5 6 Elgin, Sarah C.R.; Reuter, Gunter (August 2013). "Position-Effect Variegation, Heterochromatin Formation, and Gene Silencing in Drosophila". Cold Spring Harbor Perspectives in Biology. 5 (8): a017780. doi:10.1101/cshperspect.a017780. ISSN   1943-0264. PMC   3721279 . PMID   23906716.
  2. 1 2 3 Lloyd, Vett K.; Sinclair, Don A.; Grigliatti, Thomas A. (1999-04-01). "Genomic Imprinting and Position-Effect Variegation in Drosophila melanogaster". Genetics. 151 (4): 1503–1516. doi:10.1093/genetics/151.4.1503. ISSN   0016-6731. PMC   1460573 . PMID   10101173.
  3. ↑ Vogel, Maartje J.; Pagie, Ludo; Talhout, Wendy; Nieuwland, Marja; Kerkhoven, Ron M.; van Steensel, Bas (2009-01-29). "High-resolution mapping of heterochromatin redistribution in a Drosophila position-effect variegation model". Epigenetics & Chromatin . 2 (1): 1. CiteSeerX   10.1.1.332.4382 . doi:10.1186/1756-8935-2-1. ISSN   1756-8935. PMC   2644302 . PMID   19178722.
  4. ↑ Hermann J. Muller (1930). "Types of visible variations induced by X-rays in Drosophila". Journal of Genetics. Springer India. 22 (3): 299–334. doi:10.1007/BF02984195. S2CID   40797289.
  5. 1 2 3 4 5 6 7 Wakimoto, Barbara T (1998-05-01). "Beyond the Nucleosome: Epigenetic Aspects of Position–Effect Variegation in Drosophila". Cell. 93 (3): 321–324. doi: 10.1016/S0092-8674(00)81159-9 . PMID   9590165.
  6. ↑ Molecular biology of the cell. the United States of America: Garland Science, Taylor & Francis Group, LLC, an Informa business, 711 Third Avenue, New York, NY 10017, US 3 Park Square, Milton Park, Abingdon, OX14 4RN, UK. 2015. p. 195. ISBN   978-0-8153-4432-2.
  7. ↑ "position-effect".
  8. ↑ Tartof, Kenneth D.; Hobbs, Cheryl; Jones, Marilyn (1984-07-01). "A structural basis for variegating position effects". Cell. 37 (3): 869–878. doi:10.1016/0092-8674(84)90422-7. PMID   6086148. S2CID   36914243.
  9. ↑ Henderson, D S; Banga, S S; Grigliatti, T A; Boyd, J B (1994-03-15). "Mutagen sensitivity and suppression of position-effect variegation result from mutations in mus209, the Drosophila gene encoding PCNA". The EMBO Journal. 13 (6): 1450–1459. doi:10.1002/j.1460-2075.1994.tb06399.x. ISSN   0261-4189. PMC   394963 . PMID   7907981.

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