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Available online at www.sciencedirect.com Inherited variation at the epigenetic level: paramutation from the plant to the mouse François Cuzin1,2, Valérie Grandjean1,2 and Minoo Rassoulzadegan1,2 In contrast with a wide definition of the ‘epigenetic variation’, including all changes in gene expression that do not result from the alteration of the gene structure, a more restricted class had been defined, initially in plants, under the name ‘paramutation’. It corresponds to epigenetic modifications distinct from the regulatory interactions of the cell differentiation pathways, mitotically stable and sexually transmitted with non-Mendelian patterns. This class of epigenetic changes appeared for some time restricted to the plant world, but examples progressively accumulated of epigenetic inheritance in organisms ranging from mice to humans. Occurrence of paramutation in the mouse and possible mechanisms were then established in the paradigmatic case of a mutant phenotype maintained and hereditarily transmitted by wild-type homozygotes. Together with the recent findings in plants indicative of a necessary step of RNA amplification in the reference maize paramutation, the mouse studies point to a new role of RNA, as an inducer and hereditary determinant of epigenetic variation. Given the known presence of a wide range of RNAs in human spermatozoa, as well as a number of unexplained cases of familial disease predisposition and transgenerational maintenance, speculations can be extended to possible roles of RNA-mediated inheritance in human biology and pathology. Addresses 1 Inserm U636, F-06108 Nice, France 2 Université de Nice-Sophia Antipolis, Laboratoire de Génétique du Développement Normal et Pathologique, F-06108 Nice, France Corresponding author: Cuzin, François ([email protected]) Current Opinion in Genetics & Development 2008, 18:193–196 This review comes from a themed issue on Chromosomes and expression mechanisms Edited by Sarah Elgin and Moshe Yaniv Available online 15th February 2008 0959-437X/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.gde.2007.12.004 been, however, noted. As it is often the case, they were first considered somewhat secondary aspects, better left aside ‘for further studies.’ And at some point, they reached the front. One such event was the discovery by McClintock in the 1940s of genetic transposition in maize, a notion that was to be generalized only much later to a variety of organisms. Again in maize and at about the same time, cases of non-Mendelian inheritance were reported under the name paramutation [1]. Initially, the notion was, at best, considered an interesting peculiarity of the plant. With time, significant advances were, however, registered, especially with the development of the present-day powerful molecular techniques. And more recently, inheritance of epigenetic variations was observed in the mouse, the premier experimental model of mammalian genetics [2]. Further studies will tell us to what extent the mechanisms in the plant and the mouse are alike. Real or not, some differences may be noted. For instance, the well-documented instances of paramutation in plants [3] correspond to either partial or total gene silencing, and this is also the case of somatic epigenetic regulations, such as the transcriptional inactivation of the mammalian X chromosome [4] and of heterochromatin regions of the genome [5]. By contrast, the first few cases of mouse paramutation rather appear to correspond to the upregulation of gene expression. However, the mouse and the plant share significant common features. Paramutation occurs in both the cases as a consequence of interallelic talk. It modifies the expression of a gene, the ‘paramutable’ one, when segregated from a heterozygote parent carrying a distinct allelic form, the ‘paramutagenic’ one. Unlike a typical mutation, paramutation results in quantitatively variable phenotypes, which led to the concept of a ‘rheostat’ rather than an ‘on-off’ switch of gene expression [6]. But the most remarkable property common to the plant and the animal is to involve RNA molecules as determinants of the epigenetic variation, not only at the somatic level, as it is the case of X chromosome inactivation and gene imprinting [4,5,7], but also as carriers of a hereditary information. A brief history of paramutation Paramutation: a formal definition Owing to its intrinsic beauty and unique operational power, Mendelian genetics dominated 20th-century biology and is still at the core of biomedical science. Inheritance of the mutations – modifications of the primary genetic text – is determined by the strict rules of the chromosome ballet at meiosis. Exceptions had www.sciencedirect.com 1. Discovery in plants. The thought provoking paper by RA Brink [1] started with the statement ‘‘Departures from the law [of Mendel] have been reported from time to time, only to prove unfounded, in most instances at least, on close analysis. The present study is concerned with a seeming exception to the rule. . ..’’ Current Opinion in Genetics & Development 2008, 18:193–196 194 Chromosomes and expression mechanisms The ‘seeming exception’ was that the plant color determined by one particular allele was modified in segregants from heterozygote parents with defined allelic combinations. The altered form of the gene was maintained through the subsequent generations but eventually reversed to the original state. The author noted that this phenomenon was reminding of reversible and hereditary changes of phenotype that had been described in ascomycetes [8,9] and considered a number of possible mechanisms, including, ‘in the light of McClintock’s recent work’, integration/ excision of extrachromosomal material. The hypothesis of transposon insertion was far from absurd, as it was much later shown to be the cause of a hereditary epigenetic variation at the Agouti locus of the mouse [10]. It was not, however, to be confirmed in this case, nor in the subsequent observations of unexplained hereditary variants occurring in various plant species [3]. The term ‘paramutation’ was coined to describe this strange phenomenon [11]. It was assumed from the beginning, and fully confirmed with the progress of molecular techniques, that the affected genes were not modified in their primary structure. 2. The plant models. While observations in a number of species suggested that paramutation is not a rare event in plants, the most detailed analysis was to be performed on the maize, especially on the B0 * paramutation of the B-I locus, characterized by an extreme stability [3,6]. Epigenetic changes in B-I expression lead to a lighter color of the plant. The modified state, B0 *, is induced when the original, paramutable B-I allele is associated in a heterozygote with a paramutagenic allele. A tandemly repeated region 100 kb upstream of B-I is sufficient to induce the epigenetic modification, even in non-allelic locations. Transcribed into the non-coding RNA, it is differentially methylated and shows distinct chromatin structures in the paramutant and the wild-type genomes. A recent important finding was the identification as an RNA-dependent RNA polymerase of a gene product required for paramutation (Mop1 for Mediator Of Paramutation) [12]. A complete picture of the molecular mechanisms at work is still to be generated, but it is clear that these convergent results point to a role of RNA in the establishment and control of the epigenetic state. Inheritance of epigenetic states in the mouse 1. Interallelic cross-talk. Several indications of interallelic cross-talk in the mouse (‘paramutation-like’ effects) pointed to the possibility of non-Mendelian heredity comparable to the plant systems. One of them was the interallelic transfer of methylation patterns established after heterologous recombination during meiosis [13]. Both at the Rosa26 locus modified by the insertion of a Current Opinion in Genetics & Development 2008, 18:193–196 LoxP cassette and at the Rxra locus containing a single LoxP site, Cre expression during meiosis led to methylation in the LoxP insert. This modification extended to the neighboring regions of the same chromosome and, furthermore, was also transferred at the next generation to the un-recombined allele on the homologous chromosome. Both cis- and trans-methylation were found stably reproduced over several generations. Remarkably, they involved both CpG methylations and the methylation of other di-nucleotides in hereditary stable patterns [14]. Interallelic crosstalk was independently observed at the imprinted Rasgrf1 locus [15]. A repeated DNA element upstream of the transcription start is required to establish methylation and then expression of the active paternal allele. When this region had been replaced by one that controls methylation and allele-specific expression of the imprinted Igf2r gene, paternal inheritance of the mutated Rasgrf1 locus allowed the expression of the paternal locus, but it also caused the activation of the wild type, normally silent maternal allele. Again, transactivation was heritable and reversible. 2. Agouti and Axin-fused: transposon directed epigenetic states. A distinct instance of transgenerational maintenance of an epigenetic variation was observed at the Agouti viable yellow (Avy) and the Axin-fused (AxinFu) loci of the mouse [10]. Variation of the phenotype is linked at the two loci to the DNA methylation state of a retrotransposon responsible for their abnormal expression. The parental phenotype is transmitted either both maternally and paternally (Avy) or only maternally (AxonFu). Unlike the typical cases of paramutation, these variations do not appear, however, to involve interallelic cross-talk. 3. The Kit* paramutation [2]. Null mutants of the Kit gene are lethal in the homozygous state, while heterozygotes with a wild-type allele exhibit characteristic white spots, white tail tips and white feet in the case of a null mutant created by the insertion of a LacZ cassette [16]. In the progeny of intercrosses between heterozygotes or crosses with a wild-type partner, the fraction that inherited two wild-type (Kit+) alleles, estimated from the distribution of tail colors, appeared strangely reduced. Upon analysis, it became apparent that a Kit+/+ offspring was indeed generated but that most of it maintained the mutant phenotype. Furthermore, these genotypically wild-type mice efficiently transmitted their white spots to their progeny. Molecular analysis of Kit expression indicated a complex situation. Levels of transcripts were reduced owing to post-transcriptional cleavage. At the same time, however, the overall rate of transcription was increased, in all somatic cells and most strikingly, in the testicular post-meiotic germ cells in which the gene is normally silent. In crosses with normal wild-type partners, the modified (Kit*) state was transmitted, both maternally and paternally. Given the apparently www.sciencedirect.com Inherited variation at the epigenetic level: paramutation from the plant to the mouse Cuzin, Grandjean and Rassoulzadegan 195 simple structure of the sperm genome, paternal transmission raised the question of the signal that induces paramutation in the embryo. Suggested by the unusual amounts of RNA in the sperm of heterozygotes and Kit* males, its crucial role was established by microinjection in wild-type one-cell embryos. Injecting RNA from somatic and germ cells of heterozygotes resulted in a high frequency of establishment of the epigenetic change, while RNA of a normal mouse exhibited only a low efficiency. Another observation of interest was that two microRNAs with sequences partially complementary to that of Kit RNA (miR-221 and -222) induced the paramutated state. A variety of other microRNAs tested in the same way were fully negative as far as Kit expression was concerned (our unpublished results). On the contrary, microRNA levels were not modified in the paramutants, thus making unlikely that the modified expression of the gene was due to one of their known activities in post-transcriptional regulation, a point that will be discussed in a subsequent section. Other instances of paramutation in the mouse In order to extend the panel of phenotypes possibly altered by paramutation, a series of tissue- and organspecific microRNAs were injected in normal 1-cell embryos. Heritable epigenetic changes of distinct phenotypes were so far observed in two cases, miR-1 and miR-124. The interest of the ‘miR-1* paramutation’ is that it recapitulates several of the characteristics of a known, serious human pathology—moreover one that is known for its familial occurrence with complex patterns not amenable to a simple Mendelian scheme (K Wagner, N Wagner, H Ghanbarian, P Gounon, VG, FC & MR, manuscript in preparation). The microRNA is normally expressed in myocytes, both in the heart and the skeletal muscles. Mice born after the microinjection of miR-1 in one-cell embryos showed much enlarged hearts (hypertrophic cardiomyopathy), a condition that in humans may lead to premature death. In the ‘miR-1* paramutants’, it resulted from increased expression of the RNA encoding the Cdk9 kinase, the main effector of normal and pathological development of the heart [17]. Heart hypertrophy was efficiently inherited for several generations, both paternally and maternally, with a variable quantitative expression. RNA was carried in the spermatozoon head, including minute amounts of miR-1 sequences. Among other hereditary epigenetic variations generated by the same strategy, families derived after the microinjection of the brain-specific microRNA miR-124 and showing an accelerated growth starting at a very early developmental stage are currently under study. A role of paramutation in human heredity? Among many tantalizing questions for which there is no answer yet is the possibility that epigenetic heredity might play a significant role in humans. A familial mode www.sciencedirect.com of hereditary transmission of a disease-prone condition is conceivable on the model of the mouse paramutation, the closest one so far being the miR-1-induced cardiac hypertrophy. There is also little doubt that it will be extremely difficult to demonstrate such a proposition. Beside the obvious limitations to experimental approaches, the extreme heterogeneity of our fully outbred genomes will constitute a considerable limitation. A handful of observations are nevertheless pointing to that possibility. Transfer of RNA by the male gamete has been demonstrated (reviewed in reference [18]). Human sperm contains in fact much greater amounts of RNA than that of a ‘normal’ laboratory mouse (P. Gounon, VG, MR & FC, unpublished observations). It is tempting to speculate about these relatively high amounts of RNA being related to the extensive degree of heterozygosis of our genomes compared to those of the inbred laboratory strains. On the contrary, expression of a pathological trait dependent on the heterozygote structure in the parental generation was observed for the insulin VLTR gene in type 1 diabetes [19]. Several recently reported instances of heritable epimutations, reviewed and discussed by Whitelaw and her colleagues [20,21], may or may not belong to the same class as the typical mouse and plant paramutations. Indications are also provided by epidemiological studies, with for instance the familial occurrence of several malignancies for which no clear Mendelian heredity has been established [22] and the intriguing case of the paternal transmission of mortality risk ratios over several generations in the ‘Överkalix cohort’ [23]. There is clearly a long way to go before clear cases of paramutation can be established beyond any doubt in humans. The hope is that a more advanced knowledge of the mouse models may provide in the future useful clues and criteria to apply to clinical situations. Toward molecular mechanisms? Coming back to more immediate issues, the mechanism leading to the establishment of the paramutated state in mice is still difficult to understand within the frame of our current concepts. In spite of the fact that the microinjection of miR-1 or miR-221 RNAs was a potent inducer, several characteristics of the epigenetic modification make it difficult to relate them to one of the known activities of microRNAs. Levels of the microRNAs were not modified in the somatic and germ cells of Kit* animals, and the upregulation of gene transcription of the Kit locus in germ cells [2] cannot be simply explained by a microRNA effect. Moreover, the epigenetic modification could be induced by the microinjection of oligoribonucleotides mimicking segments of the coding sequence. The conditions that lead to paramutation – RNA transfer by sperm, by microinjection, a parental heterozygous structure with a structurally modified allele – result in the presence of abnormal transcripts in the newly formed embryo. It would then be logical to consider that they are detected by a highly sensitive surveillance mechanism that initiates a Current Opinion in Genetics & Development 2008, 18:193–196 196 Chromosomes and expression mechanisms hereditary program for protecting the embryos by an augmented expression of the normal allele. The modified expression thus established is likely to correspond to local modifications of the chromatin structure in regulatory elements, possibly at distant locations, as it is the case in the B0 * paramutation of maize. The identification of these primary targets would be an important step in our understanding of the mechanisms at work. Acknowledgements We are indebted to P Gounon, K Wagner and N Wagner for communicating the unpublished data and fruitful discussions. Work performed in our laboratory was made possible by grants from Agence Nationale de la Recherche and as ‘‘Equipe Labellisée’’ of Ligue Nationale Française contre le Cancer (France). References and recommended readings Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Brink RA: A genetic change associated with the R locus in maize which is directed and potentially reversible. Genetics 1956, 41:872-879. Of historical interest as the first clear-cut demonstration that, contrary to the established ways of thinking of the time, heredity was not to be completely explained by the Mendelian rules. 2. Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F: RNA-mediated non-Mendelian inheritance of an epigenetic change in the mouse. Nature 2006, 431: 469-474. The first complete description of a mode of heredity in a mammalian organism similar in many aspects to the paramutation of the plant geneticists. 3. Chandler VL, Stam M: Chromatin conversations: mechanisms and implications of paramutation. Nat Rev Genet 2004, 5:532-544. 4. Masui O, Heard E: RNA and protein actors in X-chromosome inactivation. Cold Spring Harb Symp Quant Biol 2006, 71:419-428. 5. Zaratiegui M, Irvine DV, Martienssen RA: Noncoding RNAs and gene silencing. Cell 2007, 128:763-776. 6. Chandler VL: Paramutation: RNA-mediated instructions passed across generations. Cell 2007, 23:641-645. The most recent review of the experimental evidences for RNA-mediated inheritance comparing the plant and the mouse systems. 7. 8. Pauler F, Koerner M, Barlow D: Silencing by imprinted noncoding RNAs: is transcription the answer? Trends Genet 2007, 23:284-292. Mitchell MB: Further evidence of aberrant recombination in Neurospora. Proc Natl Acad Sci U S A 1955, 41:935-937. Current Opinion in Genetics & Development 2008, 18:193–196 9. Rizet G: Les phénomènes de barrage chez Podospora anserina. Rev Cytol Biol Veg 1952, 13:51-92. 10. Blewitt ME, Vickaryous NK, Paldi A, Koseki H, Whitelaw E: Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet 2006, 2:e49. 11. Brink RA: Paramutation. Annu Rev Genet 1973, 7:129-152. 12. Alleman M, Sidorenko L, McGinnis K, Seshadri V, Dorweiler JE, White J, Sikkink K, Chandler VL: An RNA-dependent RNA polymerase is required for paramutation in maize. Nature 2006, 442:295-298. Establishes the notion that RNA amplification plays a role in a nonMendelian hereditary change in maize. 13. Rassoulzadegan M, Magliano M, Cuzin F: Transvection effects involving DNA methylation during meiosis in the mouse. EMBO J 2002, 21:440-450. 14. Grandjean V, Yaman R, Cuzin F, Rassoulzadegan M: Inheritance of an epigenetic mark: the CpG DNA methyltransferase 1 is required for de novo establishment of a complex pattern of non-CpG methylation. Plos One 2007, 2:e1136. 15. Herman H, Lu M, Anggraini M, Sikora A, Chang Y, Yoon BJ, Soloway PD: Trans allele methylation and paramutation-like effects in mice. Nat Genet 2003, 34:199-202. 16. Bernex F, De Sepulveda P, Kress C, Elbaz C, Delouis C, Panthier JJ: Spatial and temporal patterns of c-kit-expressing cells in WlacZ/+ and WlacZ/WlacZ mouse embryos. Development 1996, 122:3023-3033. 17. Sano M, Abdellatif M, Oh H, Xie M, Bagella L, Giordano A, Michael LH, DeMayo FJ, Schneider MD: Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. Nat Med 2002, 8:1310-1317. 18. Miller D, Ostermeier GC, Krawetz SA: The controversy, potential and roles of spermatozoal RNA. Trends Mol Med 2005, 11:156-163. An up-to-date summary of the observation of the human sperm RNA and speculations on its possible functions. 19. Bennett ST, Wilson AJ, Esposito L, Bouzekri N, Undlien DE, Cucca F, Nistico L, Buzzetti R, Bosi E, Pociot F et al.: Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group. Nat Genet 1997, 17:350-352. 20. Chong S, Whitelaw E: Epigenetic germline inheritance. Curr Opin Genet Dev 2004, 14:692-696. 21. Chong S, Yougson NA, Whitelaw E: Heritable germline epimutation is not the same as transgenerational epigenetic inheritance. Nat Genet 2007, 39:574-575. 22. Czene K, Lichtenstein P, Hemminki K: Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family—cancer database. Int J Cancer 2002, 99:260-266. 23. Pembrey M, Bygren L, Kaati G, Edvinsson S, Northstone K, Sjöström M, Golding J: ALSPAC Study Team: sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006, 14:159-166. www.sciencedirect.com