Transposon silencing

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Transposon silencing is a form of transcriptional gene silencing targeting transposons. Transcriptional gene silencing is a product of histone modifications that prevent the transcription of a particular area of DNA. Transcriptional silencing of transposons is crucial to the maintenance of a genome. The “jumping” of transposons generates genomic instability and can cause extremely deleterious mutations. Transposable element insertions have been linked to many diseases including hemophilia, severe combined immunodeficiency, and predisposition to cancer. The silencing of transposons is therefore extremely critical in the germline in order to stop transposon mutations from developing and being passed on to the next generation. Additionally, these epigenetic defenses against transposons can be heritable. Studies in Drosophila , Arabidopsis thaliana , and mice all indicate that small interfering RNAs are responsible for transposon silencing. In animals, these siRNAS and piRNAs are most active in the gonads.

Contents

Mechanism

Piwi-interacting RNA (piRNA), the largest class of the small RNAs, are between 26 and 31 nucleotides in length and function through interactions with piwi proteins from the Argonaute protein family (gene silencing proteins). Many piRNAs are derived from transposons and other repeated elements, and therefore lack specific loci. Other piRNAs that do map to specific locations are clustered in areas near the centromeres or telomeres of the chromosome. piRNA clusters make up ~1% of the genome. [1] It is thought that piRNA-PIWI complexes directly control the activity of transposons. piRNAs bound to PIWI proteins seem to use post-transcriptional transcript destruction to silence transposons. [1] Transposon insertions in introns can escape silencing via the piRNA pathway, suggesting that transcript destruction by piRNAs occurs after nuclear export. piRNAs could, however, act on multiple levels, including guiding heterochromatin assembly and possibly playing a role in translation as well . The exact biogenesis of piRNAs is still unknown. Most piRNAs are antisense to mRNAs transcribed from the silenced transposons, generally associating with Piwi and Aubergine (Aub) proteins, while sense-strand piRNAs tend to associate with Argonaute 3 (Ago3) instead. [1] A cycle called “ping pong” amplification proceeds between the sense and anti-sense piRNAs involving extensive trimming and processing to create mature piRNAs. This process is responsible for the production of most piRNAs in the germline and could also explain the origin of piRNAs in germline development. [2]

History

piRNAs were first observed in Drosophila in 1990. [3] In 2003, piRNAs derived largely from repeated sequence elements, including transposons, were found in abundance in male and female Drosophila germlines. [4] Since then, several studies have identified various piRNAs and piwi-pathways involved in transposon silencing in various species. Two such genome defense systems against transposons are the silencing of the MuDR transposon in maize and the silencing of P elements in Drosophila.

MuDR

In 2006, a study by Margaret Roth Woodhouse, Michael Freeling, and Damon Lisch identified a gene that inhibits the transcription of both transposons and paramuted color gens in maize. [5] The gene, called Mediator of paramutation1 (Mop1), codes for an RNA-processing enzyme that is necessary for making the small RNAs that are responsible for silencing the transposon MuDR. A second gene, Mu killer (MuK), is then needed to establish heritable silencing. [6]

P elements

P elements are a family of transposons that recently proliferated within the genome of Drosophila melanogaster. The P elements have an extremely high transposition rate and induce sterility and abnormal gonad development in D. melanogaster. [3] The flies thus developed a maternally inherited technique for combating the invasive DNA and silencing the transposons, now known as P cytotype. P cytotype detects DNA sequences in areas of telomeric heterochromatin and silences those sequences when they are found elsewhere in the genome. This is referred to as the telomeric-silencing effect (TSE). [3] Just two P elements in the telomere are enough to suppress over 80 other copies of the P element in the genome. The cytoplasmic factor used for TSE builds up over generations and suppression of the transposons is not fully effective unless the fly's female-line ancestors have had the P element for six generations. [3]

Related Research Articles

<span class="mw-page-title-main">Transposable element</span> Semiparasitic DNA sequence

A transposable element is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transposition often results in duplication of the same genetic material. In the human genome, L1 and Alu elements are two examples. Barbara McClintock's discovery of them earned her a Nobel Prize in 1983. Its importance in personalized medicine is becoming increasingly relevant, as well as gaining more attention in data analytics given the difficulty of analysis in very high dimensional spaces.

Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules. Other functional regions of the non-coding DNA fraction include regulatory sequences that control gene expression; scaffold attachment regions; origins of DNA replication; centromeres; and telomeres. Some non-coding regions appear to be mostly nonfunctional such as introns, pseudogenes, intergenic DNA, and fragments of transposons and viruses.

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.

<span class="mw-page-title-main">Retrotransposon</span> Type of genetic component

Retrotransposons are a type of genetic component that copy and paste themselves into different genomic locations (transposon) by converting RNA back into DNA through the reverse transcription process using an RNA transposition intermediate.

<span class="mw-page-title-main">Constitutive heterochromatin</span>

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.

The RNA-induced silencing complex, or RISC, is a multiprotein complex, specifically a ribonucleoprotein, which functions in gene silencing via a variety of pathways at the transcriptional and translational levels. Using single-stranded RNA (ssRNA) fragments, such as microRNA (miRNA), or double-stranded small interfering RNA (siRNA), the complex functions as a key tool in gene regulation. The single strand of RNA acts as a template for RISC to recognize complementary messenger RNA (mRNA) transcript. Once found, one of the proteins in RISC, Argonaute, activates and cleaves the mRNA. This process is called RNA interference (RNAi) and it is found in many eukaryotes; it is a key process in defense against viral infections, as it is triggered by the presence of double-stranded RNA (dsRNA).

Subtelomeres are segments of DNA between telomeric caps and chromatin.

P elements are transposable elements that were discovered in Drosophila as the causative agents of genetic traits called hybrid dysgenesis. The transposon is responsible for the P trait of the P element and it is found only in wild flies. They are also found in many other eukaryotes.

<span class="mw-page-title-main">Mobile genetic elements</span> DNA sequence whose position in the genome is variable

Mobile genetic elements (MGEs) sometimes called selfish genetic elements are a type of genetic material that can move around within a genome, or that can be transferred from one species or replicon to another. MGEs are found in all organisms. In humans, approximately 50% of the genome is thought to be MGEs. MGEs play a distinct role in evolution. Gene duplication events can also happen through the mechanism of MGEs. MGEs can also cause mutations in protein coding regions, which alters the protein functions. These mechanisms can also rearrange genes in the host genome generating variation. These mechanism can increase fitness by gaining new or additional functions. An example of MGEs in evolutionary context are that virulence factors and antibiotic resistance genes of MGEs can be transported to share genetic code with neighboring bacteria. However, MGEs can also decrease fitness by introducing disease-causing alleles or mutations. The set of MGEs in an organism is called a mobilome, which is composed of a large number of plasmids, transposons and viruses.

<span class="mw-page-title-main">Argonaute</span> Protein that plays a role in RNA silencing process

The Argonaute protein family, first discovered for its evolutionarily conserved stem cell function, plays a central role in RNA silencing processes as essential components of the RNA-induced silencing complex (RISC). RISC is responsible for the gene silencing phenomenon known as RNA interference (RNAi). Argonaute proteins bind different classes of small non-coding RNAs, including microRNAs (miRNAs), small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs). Small RNAs guide Argonaute proteins to their specific targets through sequence complementarity, which then leads to mRNA cleavage, translation inhibition, and/or the initiation of mRNA decay.

Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNA molecules expressed in animal cells. piRNAs form RNA-protein complexes through interactions with piwi-subfamily Argonaute proteins. These piRNA complexes are mostly involved in the epigenetic and post-transcriptional silencing of transposable elements and other spurious or repeat-derived transcripts, but can also be involved in the regulation of other genetic elements in germ line cells.

<span class="mw-page-title-main">Piwi</span>

Piwi genes were identified as regulatory proteins responsible for stem cell and germ cell differentiation. Piwi is an abbreviation of P-elementInduced WImpy testis in Drosophila. Piwi proteins are highly conserved RNA-binding proteins and are present in both plants and animals. Piwi proteins belong to the Argonaute/Piwi family and have been classified as nuclear proteins. Studies on Drosophila have also indicated that Piwi proteins have no slicer activity conferred by the presence of the Piwi domain. In addition, Piwi associates with heterochromatin protein 1, an epigenetic modifier, and piRNA-complementary sequences. These are indications of the role Piwi plays in epigenetic regulation. Piwi proteins are also thought to control the biogenesis of piRNA as many Piwi-like proteins contain slicer activity which would allow Piwi proteins to process precursor piRNA into mature piRNA.

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 (H3K9me2) is the RITS complex.

RNA silencing or RNA interference refers to a family of gene silencing effects by which gene expression is negatively regulated by non-coding RNAs such as microRNAs. RNA silencing may also be defined as sequence-specific regulation of gene expression triggered by double-stranded RNA (dsRNA). RNA silencing mechanisms are conserved among most eukaryotes. The most common and well-studied example is RNA interference (RNAi), in which endogenously expressed microRNA (miRNA) or exogenously derived small interfering RNA (siRNA) induces the degradation of complementary messenger RNA. Other classes of small RNA have been identified, including piwi-interacting RNA (piRNA) and its subspecies repeat associated small interfering RNA (rasiRNA).

RNA polymerase IV is an enzyme that synthesizes small interfering RNA (siRNA) in plants, which silence gene expression. RNAP IV belongs to a family of enzymes that catalyze the process of transcription known as RNA Polymerases, which synthesize RNA from DNA templates. Discovered via phylogenetic studies of land plants, genes of RNAP IV are thought to have resulted from multistep evolution processes that occurred in RNA Polymerase II phylogenies. Such an evolutionary pathway is supported by the fact that RNAP IV is composed of 12 protein subunits that are either similar or identical to RNA polymerase II, and is specific to plant genomes. Via its synthesis of siRNA, RNAP IV is involved in regulation of heterochromatin formation in a process known as RNA directed DNA Methylation (RdDM).

RDE-1 (RNAi-DEfective 1) is a primary Argonaute protein required for RNA-mediated interference (RNAi) in Caenorhabditis elegans. The rde-1 gene locus was first characterized in C. elegans mutants resistant to RNAi, and is a member of a highly conserved Piwi gene family that includes plant, Drosophila, and vertebrate homologs.

The gene Maelstrom, Mael, creates a protein, which was first located in Drosophila melanogaster in the nuage perinuclear structure and has functionality analogous to the spindle, spn, gene class. Its mamallian homolog is MAEL.

Transposable elements are short strands of repetitive DNA that can self-replicate and translocate within the eukaryotic genome, and are generally perceived as parasitic in nature. Their transcription can lead to the production of dsRNAs, which resemble retroviruses transcripts. While most host cellular RNA has a singular, unpaired sense strand, dsRNA possesses sense and anti-sense transcripts paired together, and this difference in structure allows an host organism to detect dsRNA production, and thereby the presence of transposons. Plants lack distinct divisions between somatic cells and reproductive cells, and also have, generally, larger genomes than animals, making them an intriguing case-study kingdom to be used in attempting to better understand the epigenetics function of transposable elements.

<span class="mw-page-title-main">Retrotransposon silencing</span>

Transposable elements are pieces of genetic material that are capable of splicing themselves into a host genome and then self propagating throughout the genome, much like a virus. Retrotransposons are a subset of transposable elements that use an RNA intermediate and reverse transcribe themselves into the genome. Retrotransposon proliferation may lead to insertional mutagenesis, disrupt the process of DNA repair, or cause errors during chromosomal crossover, and so it is advantageous for an organism to possess the means to suppress or "silence" retrotransposon activity.

<span class="mw-page-title-main">RNA-directed DNA methylation</span> RNA-based gene silencing process

RNA-directed DNA methylation (RdDM) is a biological process in which non-coding RNA molecules direct the addition of DNA methylation to specific DNA sequences. The RdDM pathway is unique to plants, although other mechanisms of RNA-directed chromatin modification have also been described in fungi and animals. To date, the RdDM pathway is best characterized within angiosperms, and particularly within the model plant Arabidopsis thaliana. However, conserved RdDM pathway components and associated small RNAs (sRNAs) have also been found in other groups of plants, such as gymnosperms and ferns. The RdDM pathway closely resembles other sRNA pathways, particularly the highly conserved RNAi pathway found in fungi, plants, and animals. Both the RdDM and RNAi pathways produce sRNAs and involve conserved Argonaute, Dicer and RNA-dependent RNA polymerase proteins.

References

  1. 1 2 3 Khurana, Jaspreet; Theurkauf, William (2010). "PiRNAs, Transposon Silencing, and Drosophila Germline Development". Journal of Cell Biology. 191 (5): 905–13. doi:10.1083/jcb.201006034. PMC   2995163 . PMID   21115802.
  2. ↑ Josse, Thibaut; Teysset, Laure; Todeschini, Anne-Laure; Sidor, Clara; Anxolabehere, Dominique; Ronsseray, Stephane (2007). "Telomeric Trans-Silencing: An Epigenetic Repression Combining RNA Silencing and Heterochromatin Formation". PLOS Genetics. 3 (9): 1633–43. doi:10.1371/journal.pgen.0030158. PMC   1976332 . PMID   17941712.
  3. 1 2 3 4 Johnson, L (2008). "Transposon Silencing: The Extraordinary Epigenetics of a Transposon Trap". Heredity. 100 (1): 5. doi: 10.1038/sj.hdy.6801064 . PMID   17895904.
  4. ↑ Theurkauf, William (2011). "Transposon Silencing of Small RNAs". Developmental Cell. 21 (2): e3. doi: 10.1016/j.devcel.2011.07.010 .
  5. ↑ Woodhouse, MR; Pedersen, B; Freeling, M (2010). "Transposed genes in Arabidopsis are often associated with flanking repeats". PLOS Genet. 6 (5): e1000949. doi:10.1371/journal.pgen.1000949. PMC   2869330 . PMID   20485521.
  6. ↑ Gross, L (October 2006). "Transposon silencing keeps jumping genes in their place". PLOS Biol. 4 (10): e353. doi:10.1371/journal.pbio.0040353. PMC   1563490 . PMID   20076477.
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