Domesticated DNA Transposon Proteins Mediate Retrotransposon Control Kathryn a O’Donnell1, 2, Jef D Boeke1, 2
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npg Cell Research (2008) 18:331-333. npg331 © 2008 IBCB, SIBS, CAS All rights reserved 1001-0602/08 $ 30.00 RESEARCH HIGHLIGHT www.nature.com/cr Domesticated DNA transposon proteins mediate retrotransposon control Kathryn A O’Donnell1, 2, Jef D Boeke1, 2 1Department of Molecular Biology and Genetics; 2The High Throughput Biology Center, The Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA. [email protected] Cell Research (2008) 18:331-333. doi: 10.1038/cr.2008.34; published online 3 March 2008 The Schizosaccharomyces pombe and provide an abundant source of to have redundant roles in centromeric genome, like those of many eukaryotes, siRNAs that are generated by RNAi ef- heterochromatin formation and chromo- contains a number of retrotransposable fector proteins. Hansen and colleagues some segregation, the Abp1 null mutant repeat sequences. The pombe elements, tested the effects of RNAi and histone exhibits a slow growth phenotype that is termed Tf1 (transposon of fission yeast deacetylase mutations on the expres- exacerbated by the loss of other CENP- 1) and Tf2 possess long terminal re- sion of Tf2 retrotransposons [3]. Tf2 B proteins, suggesting there might be peats (LTRs) and belong to the gypsy mRNA expression was not affected by additional functions for these proteins family of retrotransposons [1]. This RNAi mutants. In contrast, Tf2 mRNA in S. pombe. In an ironic twist, the class of potentially deleterious mobile expression increased in the class II work of Cam et al. suggests that these elements inserts at new genomic loca- histone deacetylase clr3Δ and the class transposase-derived proteins have been tions by reverse transcription of an RNA I histone deacetylase clr6Δ mutants, recruited to silence retrotransposons. intermediate. These and other mobile suggesting RNAi-independent regula- To further understand the signifi- elements have a significant impact tion of Tf2 chromatin structure. In the cance of the distinct phenotypes of on gene structure and influence gene current study, Grewal and colleagues the CENP-B mutants, Cam et al. first expression. Therefore, S. pombe is further investigated RNAi-independent mapped the chromosomal distribution under robust selective pressure to limit mechanisms that regulate transposon of these factors using chromatin immu- rampant transposition. activity [4]. noprecipitation followed by microarray Several modes of transposon control Throughout evolution, a protein may (ChIP-chip) analysis. Consistent with exist in different organisms. DNA meth- be co-opted or exapted for the benefit of earlier studies, Abp1 was found at ARS ylation is one important mechanism the host organism, whereby an existing sites and centromeres [6-8]. Surpris- demonstrated to regulate transposon biological feature will be adapted for ingly, both Abp1 and Cbh1 were also activity in plants, mammals, and fungi. a novel purpose. In nature, there are seen to be enriched at 5′ and 3′ LTRs of Additionally, the RNA interference several examples in which mobile DNA Tf2 retrotransposons. These proteins (RNAi) pathway is known to silence element proteins provided a source for were also detected at solo LTRs, as transposons in plants and in C. elegans. new cellular functions [5]. One well- well as other sequences not related to However, the RNAi machinery has a known example of host domestication retrotransposons. surprisingly minor role in silencing of a transposon-encoded protein is hu- The authors then asked whether loss transposable elements in S. pombe. man CENP-B, which is derived from the of CENP-B homologues influenced the In fission yeast, the RNAi machinery transposase of pogo DNA transposons. expression of these target loci. Interest- represses transcription through recruit- This protein binds to repeats within ingly, Tf2 expression increased by more ment of histone-modifying enzymes alpha satellite DNA and facilitates the than 10-fold in the abp1Δ strain. Loss of to chromatin. This occurs when the formation of centromeres. The human Abp1 also increased expression of wtf heterochromatin machinery targets protein is highly conserved and has elements (a type of repeat often adjacent certain classes of repeats at centromeres, orthologues in other systems. Three to Tf element LTRs) and genes associat- telomeres, the mat locus, and rDNA CENP-B homologues are present in S. ed with LTRs. While the loss of Cbh1 or [2]. Each of these regions contains dg pombe and are encoded by Abp1, Cbh1, Cbh2 alone did not alter Tf2 expression, and dh repeats which are transcribed and Cbh2. While they have been shown deletion of one or both of these genes www.cell-research.com | Cell Research npg 332 in the abp1Δ cells resulted in further mine whether Tf2 elements were also dition to silencing LTR retrotransposons increases in Tf2 expression. Grewal and organized into these structures, Grewal through recuitment of histone deacety- colleagues therefore suggest a model in and colleagues performed FISH analysis lases, CENP-B proteins also suppress which Abp1 may recruit Cbh1 and Cbh2 using probes specific for the Tf2 coding homologous recombination of these to Tf2 retrotransposons. As one might region. Although there are 13 full-length elements with endogenous LTRs. predict from this model, Cbh1 binding Tf2 elements in S. pombe, only 1-2 Tf2 Lastly, the authors tested whether this was not detected at Tf2 elements in foci were detected per nucleus in the CENP-B-mediated surveillance mecha- abp1Δ cells, while Abp1 binding to Tf2 majority of WT cells, suggesting that nism could also silence an extinct Tf1 persisted in the cbh1Δcbh2Δ cells. dispersed elements cluster together element integrated into the S. pombe As discussed earlier, the histone in discrete foci. Consistent with this genome. ChIP analysis demonstrated deacylases (HDACs) Clr3, a recently model, three or more of the Tf2 spots that Abp1 and Cbh1 were indeed tar- identified component of the Snf2/Hdac- were seen in CENP-B mutant strains geted to a locus where a Tf1 element containing repressor complex (SHREC), although it is puzzling why all 13 ele- was inserted into a euchromatic gene, and Clr6 were previously demonstrated ments were not detected. The authors SPAC7D4.08. The CENP-Bs suppressed to control Tf2 expression. In this study, conclude that CENP-Bs may indeed transcription and transposition of the Cam et al. investigated the potential ge- have a role in organizing Tf2 ele- Tf1 element. Surprisingly, integration of netic interaction between these HDACs ments into these specialized structures. Tf1 altered the sub-cellular localization and Abp1 in Tf2 silencing. Notably, the As the authors point out, Tf bodies of the euchromatic gene. FISH analysis increase in Tf2 expression in double are reminiscent of Drosophila gypsy revealed that SPAC7D4.08 co-localized clr3Δ clr6Δ mutant cells was less than retrotransposons, which are ordered with Tf bodies when Tf1 was inserted that observed in abp1Δ cells or in cells into specialized “insulator” bodies to at this locus. deficient in Abp1 and either Clr3 or facilitate chromatin organization [10]. How might this surveillance mecha- Clr6. These results suggest that Abp1 Indeed, future studies are necessary to nism have evolved? The authors pro- may act upstream of the HDACS and better understand the functional role pose that since both DNA transposons function to recruit the Clr3 and Clr6 of these Tf bodies in normal cells and and LTR retrotransposons are flanked HDACs to silence Tf2. ChIP analysis in response to environmental stresses. by repeat sequences and given that showed that the binding of Abp1 to Tf2 What other proteins localize to and/or transposases are known to bind inverted was unaffected in the double HDAC regulate the organization of Tf bodies? repeats of DNA transposons, then an mutant. However Cbh1 binding at Tf2 Despite these open questions, these ancient CENP-B precursor may have was decreased in HDAC mutant cells, findings support a conserved role for evolved the ability to bind a Tf LTR suggesting that Clr3 and Clr6 may aid in transposable elements in regulating (Figure 1). This new function may the recruitment of Cbh1 to Tf2 LTRs. higher order genomic architecture. have been co-opted by the host for the The authors then asked whether In addition to Tf2 retrotransposons, purpose of controlling retroelement Abp1-mediated retrotransposon silenc- the S. pombe genome also contains mobility. It is intriguing that S. pombe ing was affected by the histone chap- many LTR fragments and solo LTRs, has acquired multiple pathways for erone HIRA/Hip1, also implicated in a significant fraction of which belong retrotransposon surveillance such as that Tf2 silencing [9]. Tf2 expression was to the extinct Tf1 element family. Be- involving the Hip1 histone chaperone significantly higher in theabp1 Δhip1Δ cause the ChIP-chip analysis revealed protein and recent discoveries involving cells relative to either of the single that Abp1 and Cbh1 were also bound Hst4-mediated repression of Tf2 [12]. mutants, which implies that these gene to Tf1 LTRs, the authors reasoned that In summary, the Cam et al. study products silence Tf2 through distinct CENP-B proteins could also target extends our understanding of the role pathways. extinct Tf1 elements. They tested this of CENP-B proteins, descendents of Perhaps one of the most intriguing hypothesis by introducing a full-length DNA transposons, in retrotransposon findings of this study is the observation Tf1 element into the genome. Previous surveillance in S. pombe. There are sev- that Tf2 elements cluster into higher studies had shown that Tf1 elements eral questions raised by this study open order structures, which the authors mobilize by integrase-mediated trans- for future investigation. For example, it termed ‘Tf bodies’. Immunostaining position or homologous recombination will be interesting to determine whether analysis with Myc-tagged CENP-Bs [11]. Interestingly, a dramatic increase CENP-Bs interact with additional pro- revealed that these proteins displayed in the frequency of genomic insertions teins that are required for surveillance of a previously unrecognized complex by Tf1 was detected in CENP-B mutant transposable elements.