Briefings in Functional Genomics Advance Access published March 24, 2014
B RIEFINGS IN FUNC TIONAL GENOMICS . page 1 of 8
doi:10.1093/bfgp/elu007
Drosophila epigenome reorganization during oocyte differentiation and early embryogenesis Nicola Iovino
Abstract
Keywords: oocyte differentiation; totipotency; transgenerational epigenetic inheritance
INTRODUCTION Gametes are among the most highly specialized cells produced during development, and they perform the fundamental role of carrying the genetic information necessary for the establishment of a new life [1]. To generate such specialized cells, a tight control of transcriptional output is necessary. While it has been reported that the landscape of histone modifications changes throughout gamete differentiation, how they contribute to transcriptional control and what their functional role is remains unclear [2–5]. After fertilization, the male and female gametes fuse together and generate totipotent nuclei able to differentiate into any cell type of the developing organism. In order to reset their chromatin to a totipotent state, the gametes undergo a process of reprogramming that erases most of their epigenetic information [6–10]. It is currently unknown how totipotency is acquired and which maternal determinants govern reprogramming. Furthermore,
recent data suggest that gamete reprogramming is not complete, as, for example, a portion of the genome retains some chromatin marks [11–13]. However, it remains unclear what function these chromatin marks have during gametogenesis and early embryogenesis, and to what extent histone modifications are inherited or reprogrammed in the early embryo.
MAIN CONTENT Oocyte Specification and Determination in the Drosophila Germline During Drosophila gametogenesis, the germ cells undergo mitosis and meiosis, as well as several fate decisions. The Drosophila ovary is composed of 16– 20 ovarioles, each of which progressively assembles mature egg chambers. This continuous process is maintained by germline stem cell (GSC) pools residing at the anterior tip of the ovariole, in a region
Corresponding author. N. Iovino, Institut de Ge´ne´tique Humaine, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France and Max-Planck Institute of Immunobiology and Epigenetics, Stu¨beweg 51, 79108 Freiburg im Breisgau, Germany. Tel: þ49 761 5108 564; Fax: þ49 761 5108 566; E-mail: [email protected] Nicola Iovino is a junior group leader interested in epigenetic mechanisms acting in the germline and in the early embryo. ß The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
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In sexually reproducing organisms, propagation of the species relies on specialized haploid cells (gametes) produced by germ cells. During their development in the adult germline, the female and male gametes undergo a complex differentiation process that requires transcriptional regulation and chromatin reorganization. After fertilization, the gametes then go through extensive epigenetic reprogramming, which resets the cells to a totipotent state essential for the development of the embryo. Several histone modifications characterize distinct developmental stages of gamete formation and early embryonic development, but it is unknown whether these modifications have any physiological role. Furthermore, accumulating evidence suggests that environmentally induced chromatin changes can be inherited, yet the mechanisms underlying zygotic inheritance of the gamete epigenome remain unclear. This review gives a brief overview of the mechanisms of transgenerational epigenetic inheritance and examines the function of epigenetics during oogenesis and early embryogenesis with a focus on histone posttranslational modifications.
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Iovino Absence of other SET domain-containing proteins with histone methyl transferase functions, such as Eggless (Egg) and SU(VAR)3-9, also causes oogenesis defects, though the role of these proteins in oocyte specification or determination is unclear [4, 23]. Egg and SU(VAR)3-9 methylate histone H3 at its K9 residue, which leads to trimethylation (H3K9me3), a transcriptional repressive chromatin mark associated with heterochromatin. Egg is expressed mainly in the GSCs and in early germline cysts, whereas SU(VAR)3-9 expression is higher in differentiated egg chambers. These complementary expression patterns suggest that SU(VAR)3-9 takes over Egg’s function in methylating H3K9 at midoogenesis [23, 24]. Consistent with this, mutations in egg or in Su(var)3-9 abolish H3K9me3 in germ cells in the germarium and in developing egg chambers, respectively. Moreover, egg (and its cofactor windei) mutations, but not Su(var)3-9 mutations, cause a sterility phenotype associated with defects in controlling GSCs maintenance [24, 25]. Interestingly, Egg remains strongly expressed in the oocyte nucleus, raising the possibility that it might contribute for transcriptional repression in the oocyte [4]. Another histone modifier was recently found to be required for correct germline development: scrawny, a deubiquitinase of histone H2B. Ubiquitination of H2B is often associated with transcriptional activation. By deubiquitinating H2B in the GSCs, Scrawny prevents the premature expression of key differentiation genes, including Notch target genes [26], although a role for Scrawny in oocyte differentiation and transcriptional silencing remains to be elucidated. Histone methylations are not irreversible modifications, and several classes of histone demethylases can contribute to the establishment of correct patterns of methylation [27]. Recently, it has been shown that the Drosophila orthologs of the histone demethylase LSD1 (dLsd1, which specifically demethylates H3K4me2 and H3K4me1) and of the Jarid 1 family of JmjC domain-containing proteins (Lid, which specifically demethylates H3K4me3 and H3K4me2) cause severe sterility defects [27–29]. dLsd1 mutations do not interfere with correct oocyte determination, though it remains unclear whether Lid has any role in this process [30]. Interestingly, sterility phenotypes were also observed in Caenorhabditis elegans mutants for spr-5, one of the worm orthologs of LSD1 [31].
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called the germarium. GSCs divide asymmetrically to self renew and to produce a cystoblast. The cystoblast undergoes four rounds of mitosis with incomplete cytokinesis to form a cyst of 16 germline cells interconnected by stable cytoplasmic bridges called ‘ring canals’. One of these cells is specified and differentiates into the oocyte, whereas the other 15 cells become polyploid nurse cells [14–16]. Oocyte commitment occurs in two steps. In the first phase, 2 of the 16 germ cells (pro-oocytes) are specified, but not fully committed yet, to an oocyte fate. Therefore, in this phase, the presumptive oocytes can still revert fate (as naturally occurs for one of the pro-oocytes). This phase corresponds to the start of a meiotic program and the concentration of specific components, called oocyte determinants, in the vicinity of the future oocyte. Absence of any of these determinants precludes oocyte commitment and leads to the production of a sterile egg chamber with 16 polyploid cells [17–21]. In the second phase, one of the pro-oocytes is selected to become the oocyte through an unknown mechanism, and its identity is made largely irreversible. Progression into meiosis requires extensive reorganization of the genome. For instance, several studies have shown that histone modifications have a key function in preparing chromatin for the meiotic phase [3]. However, even though the oocyte has an extremely condensed karyosome and mostly lacks transcription, little is known about the role of histone modifiers during oocyte fate commitment. Several factors have been shown to be required for oocyte determination, but only recently has a chromatin determinant been associated with this process. The Polycomb Repressive Complex 2 (PRC2) belongs to the Polycomb group (PcG) proteins, which were first identified in Drosophila as being essential for the maintenance of Hox gene silencing [22]. The PRC2 complex contains a SET domain protein (enhancer of zeste E(z)) that catalyzes transcriptional repression-associated histone H3 lysine trimethylation (H3K27me3). In the Drosophila germline, absence of PRC2 components leads to the trans-determination of the oocyte into a polyploid cell of nurse cell-like identity. Cyclin E and the cyclin-dependent kinase inhibitor dacapo are the two cell-cycle genes that must be directly repressed by PRC2 (through the H3K27me3 repressive mark) in order to prevent the oocyte from undergoing trans-determination [5].
Drosophila Germline Epigenome
Epigenetic Control of Early Embryogenesis Embryos develop from the fusion of two highly specialized haploid germ cells—the oocyte and the sperm. In Drosophila and mouse models, immunofluorescence-based studies show that upon fertilization, the gamete genomes initially remain physically separate and undergo distinct chromatin changes [12, 37–40]. The paternal genome exchanges protamines with histones, whereas the maternal genome maintains some of the histone modifications acquired during oocyte growth, such as methylation on H3K27me3 and H3K9me3 [41, 42], and this has also been observed in flies (N. Iovino and G. Cavalli, unpublished results). After these initial events, the embryo genome undergoes extensive nuclear reorganization and epigenetic resetting, which are essential for totipotency. The acquisition of developmental potency is thought to arise from
reprogramming of the parental gametes’ epigenetic state, although a thorough understanding of this mechanism is still lacking. Furthermore, the extent to which chromatin is reprogrammed or maternally inherited in early embryogenesis remains unknown, leaving open the question of how much epigenetic information from the mature gametes is retained in the embryo and is required for totipotency. In Drosophila, only a few reports address the function of epigenetic modifiers in sperm decondensation after fertilization, and the nuclear events required for reprogramming after pronuclear fusion have never been described [40, 43]. It has long been established that totipotent nuclei from Drosophila syncytial embryos can give rise to an organism, and that unfertilized eggs can reprogram somatic cells to a totipotent state [7]. Since reprogramming takes place in the egg, maternal components must be involved in this process. PcG proteins have been involved in the early reprogramming events in mouse models. PRC1 components have been shown to be expressed in the germline to convey transcriptional control of specific genes that are maternally contributed to the embryo. Loss of PRC1 in the maternal germline caused embryonic arrest at two-cell stage. Most interestingly, by elegant chromosome transfer experiments, it has been shown that the chromatin states specified by PRC1 during oocyte growth are required for embryo development, strengthening the hypothesis that a pre-patterned chromatin state is inherited from the germline and is required for faithful gene repression in the early embryo [44]. Understanding which genes inherit repressed or active states from the maternal germline and which are the epigenetic modifiers involved in the process may give us some insight into the role of epigenetics during totipotency establishment.
Transgenerational Epigenetic Inheritance Recent studies have reported the phenomena of transgenerational epigenetic inheritance (TEI), which is usually referred to as the transmission of epigenetic information from one generation to the next. The ability of the epigenome to sense and react to the environment makes it an ideal candidate for short-term adaptation (Figure 1) [45, 46]. Examples of natural occurring epialleles (i.e. an allelic form of a gene whose transcriptional activity is dependent on its epigenetic state rather than nucleotide changes)
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During differentiation, the oocyte undergoes a profound nuclear reorganization, with the karyosome assuming an extremely compacted and condensed conformation. ATP-dependent chromatin-remodeling enzymes could provide a means of generating such changes in chromatin structure. In Drosophila, there are five ATP-dependent remodeling factors: Brahma (BRM), Imitation SWI (ISWI), Domino (DOM), Kismet (KIS) and dMi-2, all sharing an SNF2-related domain and a DEAD/ DEAH-box helicase domain [32]. dom and iswi are required for normal oogenesis, and more recently it was reported that they are involved in GSCs and somatic stem cells regulation [33–35]. It would be interesting to investigate the eventual involvement of ATP-dependent remodeling factors in oocyte karyosome compaction and in its transcriptional silencing. Histone modifications have an important role in transcriptional control [36]. Given the transcriptional regulation and chromatin condensation the oocyte encounters during its meiotic path, it will be interesting to dissect the function of all the histone modifications (H3K27me3, H3K27ac, H3K9me3, H2AT119p, H1p, H3ac, H4ac, H4K5ac, H3K14ac and H4K12ac) that have been found associated with the oocyte (Figure 1) [3–5]. Moreover, characterizing oocyte epigenome and its contribution to the early embryo chromatin will shed light on the role of histone modifications in the phenomena of transgenerational epigenetic inheritance.
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Figure 1: Confocal image of a Drosophila ovariole (dark gray) overlaid on a ‘Waddington landscape’. The ovariole differentiates starting from the GSC niche (represented as a castle) with increasingly big and more developed egg chambers toward the bottom of the figure. The oocyte histone landscape is represented as a crown. During differentiation, the oocyte encounters several histone modifications that are mediated by specific histone modifiers (known histone modifications present on the oocyte during differentiation are highlighted in the right corner box). Environmental stresses (such as age, temperature, high salt, diet and drugs) depicted as a cloud storm are hypothesized to affect (represented as lightening) the oocyte epigenome during its differentiation in a still unknown way.
Drosophila Germline Epigenome
In C. elegans, phenomena of TEI of sterility and longevity phenotypes were also shown to be mediated by histone modifications, in particular those affecting H3K4 methylation [31, 69]. Increasing levels of H3K4me2, due to the loss of demethylase spr-5, cause more and more severe germline mortality across generations, correlating with the mis-regulation of spermatogenesisexpressed genes and the increasing levels of H3K4me2 at these loci, suggesting an intergenerational inheritance of increasing levels of H3K4me2 [31]. Mutations, instead, affecting the COMPASS complex, that trymethylates H4K4 increased C. elegans life span by a mechanism also depending on H4K4 methylation and the transcriptional misregulation of several genes related to longevity. Interestingly, F3, wild-type descendants from COMPASS-mutant parents, also showed a life span extension and mis-regulation of genes related to longevity suggesting a TEI phenomenon [69]. In mice, offspring fed on regular diet but fathered by male fed on a low-protein diet exhibited increased expression of genes involved in fat and cholesterol biosynthesis and presented low levels of H3K27me3 at specific loci, even though the phenomenon was not tested in the subsequent generations [55]. Non-coding RNAs have also been involved in TEI in flies and worms [54, 66, 71, 72]. Piwi-interacting RNAs (piRNAs) are linked to both epigenetic and post-transcriptional gene silencing of retrotransposons and other genetic elements and have also been shown to provide transgenerational memory of transposon gene silencing in the germline, a phenomenon depending on the mother age [73]. Furthermore, telomeric clusters of transgenes can induce strong trans-silencing effects on homologous non-active clusters of transgenes and activate them into strong silencers, a process also mediated by piRNAs. piRNAs inherited maternally are sufficient to trigger transgenerational silencing of transgenes for several generations [65]. Given that piRNAs can influence epigenetic marks and chromatin states, we could envisage that piRNAs-mediated transgenerational inheritance is also propagated by changes in chromatin states. In C. elegans, piRNAs can trigger stable, multigenerational silencing of transgenes [66, 71] whose maintenance and trangenerational propagation requires components of chromatin modifiers, such as the heterochromatin protein 1 (HP1) ortholog
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have been described in plants [47, 48], whereas in mammals only a few cases of TEI phenomena have been reported, mainly in mice [49–54]. In mice, maternal-induced stress in one generation (mainly nutrition stress) can affect successive generations, although it remains to be elucidated whether these phenomena are the result of epiallele transmission through the gametes [55–57]. An unequivocal example of epigenome-dependent environmental sensing was recently described in Arabidopsis [48], but it remains to be determined whether this model can be generalized. Furthermore, the molecular nature of the epigenetic marks passing through the germline remains unknown. In Drosophila, Waddington first reported in 1952 cases of TEI from heat stress [58–60]. More recently, several examples of TEI have been associated with transgenes, heterochromatin, toxic and diet stress and non-coding RNAs in Drosophila [61–65] and C. elegans [31, 66–69]. For instance, using Drosophila transgenic lines, Cavalli and Paro showed that when Polycomb-dependent silencing induced to the Fab-7 element is released (with a short pulse of GAL4), a statistically significant increase in this new active state can be transmitted meiotically, and therefore a small part of the progeny retains the active state into the following generation [61], a transgenerational activation memory that was partly mediated by histone modifications [70]. In another report, an inversion on the X chromosome that places the white gene next to pericentric heterochromatin was used to study meiotic transmission of stress-induced epigenetic states. In wild-type flies, the white gene is expressed in all eye cells (red eyes), whereas flies carrying the inversion have a variegated eye color (red-white mosaic eyes) because the white gene is expressed only in some cells. When heat shock and osmotic stress (which impair establishment and maintenance of heterochromatin) were applied to these mutant flies, the characteristic variegated-eye phenotype was lost and flies with red eyes were recovered. This phenotype (epigenetic states) can also be transmitted meiotically to the next generation [62]. In both examples above, it was shown that histone modifications and chromatin modifiers were involved in the TEI phenomena [62, 70]. More recently, Stern etal. [63] showed that toxic challenges in flies cause developmental changes that are epigenetically heritable in successive generations and are mediated, at least in part, by the PcG family regulators.
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HPL-2, and putative H3K9 methyltransferases SET25 and SET-32 [66, 74]. This observation strengthens the hypothesis that non-coding RNAs-mediated transgenerational phenomena might impinge on chromatin states. Other non-coding RNAs have been associated with phenomena of transgenerational epigenetic inheritance in C. elegans and mouse, but not in flies [75, 76]. As these different non-coding RNAs classes are present also in the fly, it would be interesting to investigate whether they play a role in Drosophila transgenerational epigenetic inheritance.
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In this review, we discussed some of the major known epigenetic events that regulate oocyte development and early embryogenesis in Drosophila. Despite recent advances in the field, our overall understanding of these epigenetic processes is still limited, especially regarding the hypothetical maternal epigenetic contributions to zygotic transcriptional activation and regulation. Maternal transmission of epigenetic states could explain phenomena of meiotic TEI, which have so far been observed mainly in retrotransposons and other repeated elements but not on coding genes. Furthermore, environmental factors could also have long-lasting effects on chromatin, yet it remains largely unknown whether (and how) the environment triggers alterations in the epigenome. There is still a long way to go, but the use of simple genetic model systems like Drosophila could speed up the dissection of the complex mechanisms underlying the crosstalk between epigenetics and the environment.
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Key Points Epigenetic events characterizing oocyte differentiation. Epigenetic inheritance in the early embryo. Transgenerational epigenetic inheritance.
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18. Acknowledgements I wish to thank Thierry Cheutin and Filippo Ciabrelli for critically reading the manuscript. I wish to thank Vincenzo Iovino and Lucina Hartley Koudelka for Figure 1 artwork. N.I. was supported by a long-term European Molecular Biology Organization fellowship and by a fellowship from the Human Frontier Science Program Organization.
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CONCLUSION AND PERSPECTIVES
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doi:10.1093/bfgp/elu007
Drosophila epigenome reorganization during oocyte differentiation and early embryogenesis Nicola Iovino
Abstract
Keywords: oocyte differentiation; totipotency; transgenerational epigenetic inheritance
INTRODUCTION Gametes are among the most highly specialized cells produced during development, and they perform the fundamental role of carrying the genetic information necessary for the establishment of a new life [1]. To generate such specialized cells, a tight control of transcriptional output is necessary. While it has been reported that the landscape of histone modifications changes throughout gamete differentiation, how they contribute to transcriptional control and what their functional role is remains unclear [2–5]. After fertilization, the male and female gametes fuse together and generate totipotent nuclei able to differentiate into any cell type of the developing organism. In order to reset their chromatin to a totipotent state, the gametes undergo a process of reprogramming that erases most of their epigenetic information [6–10]. It is currently unknown how totipotency is acquired and which maternal determinants govern reprogramming. Furthermore,
recent data suggest that gamete reprogramming is not complete, as, for example, a portion of the genome retains some chromatin marks [11–13]. However, it remains unclear what function these chromatin marks have during gametogenesis and early embryogenesis, and to what extent histone modifications are inherited or reprogrammed in the early embryo.
MAIN CONTENT Oocyte Specification and Determination in the Drosophila Germline During Drosophila gametogenesis, the germ cells undergo mitosis and meiosis, as well as several fate decisions. The Drosophila ovary is composed of 16– 20 ovarioles, each of which progressively assembles mature egg chambers. This continuous process is maintained by germline stem cell (GSC) pools residing at the anterior tip of the ovariole, in a region
Corresponding author. N. Iovino, Institut de Ge´ne´tique Humaine, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France and Max-Planck Institute of Immunobiology and Epigenetics, Stu¨beweg 51, 79108 Freiburg im Breisgau, Germany. Tel: þ49 761 5108 564; Fax: þ49 761 5108 566; E-mail: [email protected] Nicola Iovino is a junior group leader interested in epigenetic mechanisms acting in the germline and in the early embryo. ß The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
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In sexually reproducing organisms, propagation of the species relies on specialized haploid cells (gametes) produced by germ cells. During their development in the adult germline, the female and male gametes undergo a complex differentiation process that requires transcriptional regulation and chromatin reorganization. After fertilization, the gametes then go through extensive epigenetic reprogramming, which resets the cells to a totipotent state essential for the development of the embryo. Several histone modifications characterize distinct developmental stages of gamete formation and early embryonic development, but it is unknown whether these modifications have any physiological role. Furthermore, accumulating evidence suggests that environmentally induced chromatin changes can be inherited, yet the mechanisms underlying zygotic inheritance of the gamete epigenome remain unclear. This review gives a brief overview of the mechanisms of transgenerational epigenetic inheritance and examines the function of epigenetics during oogenesis and early embryogenesis with a focus on histone posttranslational modifications.
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Iovino Absence of other SET domain-containing proteins with histone methyl transferase functions, such as Eggless (Egg) and SU(VAR)3-9, also causes oogenesis defects, though the role of these proteins in oocyte specification or determination is unclear [4, 23]. Egg and SU(VAR)3-9 methylate histone H3 at its K9 residue, which leads to trimethylation (H3K9me3), a transcriptional repressive chromatin mark associated with heterochromatin. Egg is expressed mainly in the GSCs and in early germline cysts, whereas SU(VAR)3-9 expression is higher in differentiated egg chambers. These complementary expression patterns suggest that SU(VAR)3-9 takes over Egg’s function in methylating H3K9 at midoogenesis [23, 24]. Consistent with this, mutations in egg or in Su(var)3-9 abolish H3K9me3 in germ cells in the germarium and in developing egg chambers, respectively. Moreover, egg (and its cofactor windei) mutations, but not Su(var)3-9 mutations, cause a sterility phenotype associated with defects in controlling GSCs maintenance [24, 25]. Interestingly, Egg remains strongly expressed in the oocyte nucleus, raising the possibility that it might contribute for transcriptional repression in the oocyte [4]. Another histone modifier was recently found to be required for correct germline development: scrawny, a deubiquitinase of histone H2B. Ubiquitination of H2B is often associated with transcriptional activation. By deubiquitinating H2B in the GSCs, Scrawny prevents the premature expression of key differentiation genes, including Notch target genes [26], although a role for Scrawny in oocyte differentiation and transcriptional silencing remains to be elucidated. Histone methylations are not irreversible modifications, and several classes of histone demethylases can contribute to the establishment of correct patterns of methylation [27]. Recently, it has been shown that the Drosophila orthologs of the histone demethylase LSD1 (dLsd1, which specifically demethylates H3K4me2 and H3K4me1) and of the Jarid 1 family of JmjC domain-containing proteins (Lid, which specifically demethylates H3K4me3 and H3K4me2) cause severe sterility defects [27–29]. dLsd1 mutations do not interfere with correct oocyte determination, though it remains unclear whether Lid has any role in this process [30]. Interestingly, sterility phenotypes were also observed in Caenorhabditis elegans mutants for spr-5, one of the worm orthologs of LSD1 [31].
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called the germarium. GSCs divide asymmetrically to self renew and to produce a cystoblast. The cystoblast undergoes four rounds of mitosis with incomplete cytokinesis to form a cyst of 16 germline cells interconnected by stable cytoplasmic bridges called ‘ring canals’. One of these cells is specified and differentiates into the oocyte, whereas the other 15 cells become polyploid nurse cells [14–16]. Oocyte commitment occurs in two steps. In the first phase, 2 of the 16 germ cells (pro-oocytes) are specified, but not fully committed yet, to an oocyte fate. Therefore, in this phase, the presumptive oocytes can still revert fate (as naturally occurs for one of the pro-oocytes). This phase corresponds to the start of a meiotic program and the concentration of specific components, called oocyte determinants, in the vicinity of the future oocyte. Absence of any of these determinants precludes oocyte commitment and leads to the production of a sterile egg chamber with 16 polyploid cells [17–21]. In the second phase, one of the pro-oocytes is selected to become the oocyte through an unknown mechanism, and its identity is made largely irreversible. Progression into meiosis requires extensive reorganization of the genome. For instance, several studies have shown that histone modifications have a key function in preparing chromatin for the meiotic phase [3]. However, even though the oocyte has an extremely condensed karyosome and mostly lacks transcription, little is known about the role of histone modifiers during oocyte fate commitment. Several factors have been shown to be required for oocyte determination, but only recently has a chromatin determinant been associated with this process. The Polycomb Repressive Complex 2 (PRC2) belongs to the Polycomb group (PcG) proteins, which were first identified in Drosophila as being essential for the maintenance of Hox gene silencing [22]. The PRC2 complex contains a SET domain protein (enhancer of zeste E(z)) that catalyzes transcriptional repression-associated histone H3 lysine trimethylation (H3K27me3). In the Drosophila germline, absence of PRC2 components leads to the trans-determination of the oocyte into a polyploid cell of nurse cell-like identity. Cyclin E and the cyclin-dependent kinase inhibitor dacapo are the two cell-cycle genes that must be directly repressed by PRC2 (through the H3K27me3 repressive mark) in order to prevent the oocyte from undergoing trans-determination [5].
Drosophila Germline Epigenome
Epigenetic Control of Early Embryogenesis Embryos develop from the fusion of two highly specialized haploid germ cells—the oocyte and the sperm. In Drosophila and mouse models, immunofluorescence-based studies show that upon fertilization, the gamete genomes initially remain physically separate and undergo distinct chromatin changes [12, 37–40]. The paternal genome exchanges protamines with histones, whereas the maternal genome maintains some of the histone modifications acquired during oocyte growth, such as methylation on H3K27me3 and H3K9me3 [41, 42], and this has also been observed in flies (N. Iovino and G. Cavalli, unpublished results). After these initial events, the embryo genome undergoes extensive nuclear reorganization and epigenetic resetting, which are essential for totipotency. The acquisition of developmental potency is thought to arise from
reprogramming of the parental gametes’ epigenetic state, although a thorough understanding of this mechanism is still lacking. Furthermore, the extent to which chromatin is reprogrammed or maternally inherited in early embryogenesis remains unknown, leaving open the question of how much epigenetic information from the mature gametes is retained in the embryo and is required for totipotency. In Drosophila, only a few reports address the function of epigenetic modifiers in sperm decondensation after fertilization, and the nuclear events required for reprogramming after pronuclear fusion have never been described [40, 43]. It has long been established that totipotent nuclei from Drosophila syncytial embryos can give rise to an organism, and that unfertilized eggs can reprogram somatic cells to a totipotent state [7]. Since reprogramming takes place in the egg, maternal components must be involved in this process. PcG proteins have been involved in the early reprogramming events in mouse models. PRC1 components have been shown to be expressed in the germline to convey transcriptional control of specific genes that are maternally contributed to the embryo. Loss of PRC1 in the maternal germline caused embryonic arrest at two-cell stage. Most interestingly, by elegant chromosome transfer experiments, it has been shown that the chromatin states specified by PRC1 during oocyte growth are required for embryo development, strengthening the hypothesis that a pre-patterned chromatin state is inherited from the germline and is required for faithful gene repression in the early embryo [44]. Understanding which genes inherit repressed or active states from the maternal germline and which are the epigenetic modifiers involved in the process may give us some insight into the role of epigenetics during totipotency establishment.
Transgenerational Epigenetic Inheritance Recent studies have reported the phenomena of transgenerational epigenetic inheritance (TEI), which is usually referred to as the transmission of epigenetic information from one generation to the next. The ability of the epigenome to sense and react to the environment makes it an ideal candidate for short-term adaptation (Figure 1) [45, 46]. Examples of natural occurring epialleles (i.e. an allelic form of a gene whose transcriptional activity is dependent on its epigenetic state rather than nucleotide changes)
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During differentiation, the oocyte undergoes a profound nuclear reorganization, with the karyosome assuming an extremely compacted and condensed conformation. ATP-dependent chromatin-remodeling enzymes could provide a means of generating such changes in chromatin structure. In Drosophila, there are five ATP-dependent remodeling factors: Brahma (BRM), Imitation SWI (ISWI), Domino (DOM), Kismet (KIS) and dMi-2, all sharing an SNF2-related domain and a DEAD/ DEAH-box helicase domain [32]. dom and iswi are required for normal oogenesis, and more recently it was reported that they are involved in GSCs and somatic stem cells regulation [33–35]. It would be interesting to investigate the eventual involvement of ATP-dependent remodeling factors in oocyte karyosome compaction and in its transcriptional silencing. Histone modifications have an important role in transcriptional control [36]. Given the transcriptional regulation and chromatin condensation the oocyte encounters during its meiotic path, it will be interesting to dissect the function of all the histone modifications (H3K27me3, H3K27ac, H3K9me3, H2AT119p, H1p, H3ac, H4ac, H4K5ac, H3K14ac and H4K12ac) that have been found associated with the oocyte (Figure 1) [3–5]. Moreover, characterizing oocyte epigenome and its contribution to the early embryo chromatin will shed light on the role of histone modifications in the phenomena of transgenerational epigenetic inheritance.
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Figure 1: Confocal image of a Drosophila ovariole (dark gray) overlaid on a ‘Waddington landscape’. The ovariole differentiates starting from the GSC niche (represented as a castle) with increasingly big and more developed egg chambers toward the bottom of the figure. The oocyte histone landscape is represented as a crown. During differentiation, the oocyte encounters several histone modifications that are mediated by specific histone modifiers (known histone modifications present on the oocyte during differentiation are highlighted in the right corner box). Environmental stresses (such as age, temperature, high salt, diet and drugs) depicted as a cloud storm are hypothesized to affect (represented as lightening) the oocyte epigenome during its differentiation in a still unknown way.
Drosophila Germline Epigenome
In C. elegans, phenomena of TEI of sterility and longevity phenotypes were also shown to be mediated by histone modifications, in particular those affecting H3K4 methylation [31, 69]. Increasing levels of H3K4me2, due to the loss of demethylase spr-5, cause more and more severe germline mortality across generations, correlating with the mis-regulation of spermatogenesisexpressed genes and the increasing levels of H3K4me2 at these loci, suggesting an intergenerational inheritance of increasing levels of H3K4me2 [31]. Mutations, instead, affecting the COMPASS complex, that trymethylates H4K4 increased C. elegans life span by a mechanism also depending on H4K4 methylation and the transcriptional misregulation of several genes related to longevity. Interestingly, F3, wild-type descendants from COMPASS-mutant parents, also showed a life span extension and mis-regulation of genes related to longevity suggesting a TEI phenomenon [69]. In mice, offspring fed on regular diet but fathered by male fed on a low-protein diet exhibited increased expression of genes involved in fat and cholesterol biosynthesis and presented low levels of H3K27me3 at specific loci, even though the phenomenon was not tested in the subsequent generations [55]. Non-coding RNAs have also been involved in TEI in flies and worms [54, 66, 71, 72]. Piwi-interacting RNAs (piRNAs) are linked to both epigenetic and post-transcriptional gene silencing of retrotransposons and other genetic elements and have also been shown to provide transgenerational memory of transposon gene silencing in the germline, a phenomenon depending on the mother age [73]. Furthermore, telomeric clusters of transgenes can induce strong trans-silencing effects on homologous non-active clusters of transgenes and activate them into strong silencers, a process also mediated by piRNAs. piRNAs inherited maternally are sufficient to trigger transgenerational silencing of transgenes for several generations [65]. Given that piRNAs can influence epigenetic marks and chromatin states, we could envisage that piRNAs-mediated transgenerational inheritance is also propagated by changes in chromatin states. In C. elegans, piRNAs can trigger stable, multigenerational silencing of transgenes [66, 71] whose maintenance and trangenerational propagation requires components of chromatin modifiers, such as the heterochromatin protein 1 (HP1) ortholog
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have been described in plants [47, 48], whereas in mammals only a few cases of TEI phenomena have been reported, mainly in mice [49–54]. In mice, maternal-induced stress in one generation (mainly nutrition stress) can affect successive generations, although it remains to be elucidated whether these phenomena are the result of epiallele transmission through the gametes [55–57]. An unequivocal example of epigenome-dependent environmental sensing was recently described in Arabidopsis [48], but it remains to be determined whether this model can be generalized. Furthermore, the molecular nature of the epigenetic marks passing through the germline remains unknown. In Drosophila, Waddington first reported in 1952 cases of TEI from heat stress [58–60]. More recently, several examples of TEI have been associated with transgenes, heterochromatin, toxic and diet stress and non-coding RNAs in Drosophila [61–65] and C. elegans [31, 66–69]. For instance, using Drosophila transgenic lines, Cavalli and Paro showed that when Polycomb-dependent silencing induced to the Fab-7 element is released (with a short pulse of GAL4), a statistically significant increase in this new active state can be transmitted meiotically, and therefore a small part of the progeny retains the active state into the following generation [61], a transgenerational activation memory that was partly mediated by histone modifications [70]. In another report, an inversion on the X chromosome that places the white gene next to pericentric heterochromatin was used to study meiotic transmission of stress-induced epigenetic states. In wild-type flies, the white gene is expressed in all eye cells (red eyes), whereas flies carrying the inversion have a variegated eye color (red-white mosaic eyes) because the white gene is expressed only in some cells. When heat shock and osmotic stress (which impair establishment and maintenance of heterochromatin) were applied to these mutant flies, the characteristic variegated-eye phenotype was lost and flies with red eyes were recovered. This phenotype (epigenetic states) can also be transmitted meiotically to the next generation [62]. In both examples above, it was shown that histone modifications and chromatin modifiers were involved in the TEI phenomena [62, 70]. More recently, Stern etal. [63] showed that toxic challenges in flies cause developmental changes that are epigenetically heritable in successive generations and are mediated, at least in part, by the PcG family regulators.
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HPL-2, and putative H3K9 methyltransferases SET25 and SET-32 [66, 74]. This observation strengthens the hypothesis that non-coding RNAs-mediated transgenerational phenomena might impinge on chromatin states. Other non-coding RNAs have been associated with phenomena of transgenerational epigenetic inheritance in C. elegans and mouse, but not in flies [75, 76]. As these different non-coding RNAs classes are present also in the fly, it would be interesting to investigate whether they play a role in Drosophila transgenerational epigenetic inheritance.
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In this review, we discussed some of the major known epigenetic events that regulate oocyte development and early embryogenesis in Drosophila. Despite recent advances in the field, our overall understanding of these epigenetic processes is still limited, especially regarding the hypothetical maternal epigenetic contributions to zygotic transcriptional activation and regulation. Maternal transmission of epigenetic states could explain phenomena of meiotic TEI, which have so far been observed mainly in retrotransposons and other repeated elements but not on coding genes. Furthermore, environmental factors could also have long-lasting effects on chromatin, yet it remains largely unknown whether (and how) the environment triggers alterations in the epigenome. There is still a long way to go, but the use of simple genetic model systems like Drosophila could speed up the dissection of the complex mechanisms underlying the crosstalk between epigenetics and the environment.
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Key Points Epigenetic events characterizing oocyte differentiation. Epigenetic inheritance in the early embryo. Transgenerational epigenetic inheritance.
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CONCLUSION AND PERSPECTIVES
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