Developmental Cell
Previews and/or glomerular ultrafiltration due to loss of specialized podocyte foot processes (Doyonnas et al., 2001). By contrast, endothelial tubulogenesis and lumen formation were normal in these animals (Doyonnas et al., 2001), despite the fact that podocalyxin is apically expressed in ECs (Dekan et al., 1990). Although it is clear that epithelial and endothelial tubulogenic mechanisms have similar features, these cell types are functionally different. The mechanisms controlling apical-basal polarization in these cells, while similar, also have distinct features (Datta et al., 2011; Davis et al., 2011; Sacharidou et al., 2012). In contrast to epithelial polarization, EC polarization depends on unique signals derived from blood flow and shear stress on the EC apical surface, the vascular basement membrane com-
posed of different laminin isoforms (compared to epithelial basement membranes), and the close association of mural cells along the basal surface (Davis et al., 2011; Sacharidou et al., 2012). Together, these studies demonstrate common themes in both epithelial and endothelial systems as to how molecular switches control cell polarization. Bryant et al. (2014) provide a key lesson for future studies using different cell types and model systems by demonstrating that detailed molecular studies are necessary to elucidate the underlying basis for complex morphogenic processes, including lumen and tube formation.
Bryant, D.M., Datta, A., Rodrı´guez-Fraticelli, A.E., Pera¨nen, J., Martı´n-Belmonte, F., and Mostov, K.E. (2010). Nat. Cell Biol. 12, 1035–1045. Bryant, D.M., Roignot, J., Datta, A., Overeem, A.W., Kim, M., Yu, W., Peng, X., Eastburn, D.J., Ewald, A.J., Werb, Z., and Mostov, K.E. (2014). Dev. Cell, in press. Published online October 8, 2014. Datta, A., Bryant, D.M., and Mostov, K.E. (2011). Curr. Biol. 21, R126–R136. Davis, G.E., Stratman, A.N., Sacharidou, A., and Koh, W. (2011). Int Rev Cell Mol Biol 288, 101–165. Dekan, G., Miettinen, A., Schnabel, E., and Farquhar, M.G. (1990). Am. J. Pathol. 137, 913–927. Doyonnas, R., Kershaw, D.B., Duhme, C., Merkens, H., Chelliah, S., Graf, T., and McNagny, K.M. (2001). J. Exp. Med. 194, 13–27.
REFERENCES
Sacharidou, A., Stratman, A.N., and Davis, G.E. (2012). Cells Tissues Organs (Print) 195, 122–143.
Bryant, D.M., and Mostov, K.E. (2008). Nat. Rev. Mol. Cell Biol. 9, 887–901.
Xu, K., Sacharidou, A., Fu, S., Chong, D.C., Skaug, B., Chen, Z.J., Davis, G.E., and Cleaver, O. (2011). Dev. Cell 20, 526–539.
Multigenerational Chromatin Marks: No Enzymes Need Apply William G. Kelly1,* 1Biology Department, Emory University, Atlanta, GA 30322, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2014.10.008
Epigenetic memory stably maintains and transmits information during genome replication. Recently in Science, Gaydos et al. (2014) show that repressive chromatin marks exhibit transgenerational stability in the absence of chromatin-modifying enzymes in Caenorhabditis elegans, in contrast to work in flies suggesting that such proteins mediate stable inheritance of epigenetic modifications. Epigenetic processes drive heritable alterations in gene expression independently of changes in DNA sequences. While changes in gene expression always occur in cells in response to alterations in their environment, epigenetic heritability requires that these changes (which can be activating or repressive) are stable during and after cell division and that they no longer requires the factor(s) that initiated the change. A classic example is the maintenance of Hox gene expression patterns in fly embryos after the initiating transcription factors are no longer present. The conserved PcG enzyme E(z) or EZH2 adds methyl
groups to histone H3 on lysine 27 (H3K27me), and trimethylation of this residue (H3K27me3) is strongly correlated with gene repression in many organisms. E(z) acts in a conserved complex, called PRC2, along with Esc/EED; EED can bind H3K27me3 and recruit the complex to its own mark in a feedforward loop: PRC2 is recruited to nucleosomes with preexisting H3K27me3 to maintain or increase its regional enrichment (Margueron and Reinberg, 2011). Recent work in C. elegans from the group of Susan Strome now provides further insight into the mechanisms underlying PRC2/H3K27me3-mediated trans-
142 Developmental Cell 31, October 27, 2014 ª2014 Elsevier Inc.
mission of epigenetic memory (Gaydos et al., 2014). The contribution of modified histones to epigenetic memory has been debated because DNA replication involves massive dilution of chromatin-associated proteins and, possibly, extensive replacement of parental histones (reviewed in Campos et al., 2014). How might any histone-based information be faithfully transferred between cell divisions, let alone between generations, in the face of such histone dynamics? One possibility is that histonemodifying complexes, rather than the histone marks themselves, are anchored to target loci. This mechanism is supported
Developmental Cell
Previews by a study in Drosophila depleted of H3K27me3 that indicated that histonebecome marked by PRC2 de modifying activities including novo in the embryo? To test PRC2, and not the modificathis, they mated males lacking tions they produce, remained PRC2 activity, and therefore associated with the daughter lacking H3K27me3 in their DNA and subsequently reessperm, to hermaphrodites tablished the marks after repliwith normal PRC2 activity cation (Petruk et al., 2012). (Figure 1B). The offspring The mechanism presumably had maternally provided relies on DNA sequence inforPRC2 activity and had also mation to provide the anchor, inherited a functional gene rather than preexisting hisfrom the oocyte. As expected, tones; in flies, this information the maternal chromosomes is provided by Polycomb were brightly decorated with response elements (PREs). H3K27me in the zygote, but The new study from Gaydos the male chromosomes were et al. (2014), however, indinot. Despite the presence of cates that in C. elegans subPRC2, however, the spermstantial H3K27me3 can derived chromosomes had remain in the daughter chrono detectable accumulation matin after replication. of H3K27me3, at least in the Furthermore, preexisting germline, for the rest of H3K27me3 is required to embryogenesis. In contrast, maintain epigenetic memory no dilution of H3K27me3 was in the germline, indicating observed in the oocytethat histone modifications derived chromatin. This is can indeed provide a heritable strong evidence that in memory not only though cell C. elegans embryos the divisions, but also across PRC2 complex maintains Figure 1. H3K27me3 Persistence and Pattern Maintenance in generations. preexisting H3K27me3 estabC. elegans Embryos and Germline The C. elegans PRC2 lished in the parental germline Gametes originating from germlines with (green-filled) or without (red-filled) complex is composed of but in the embryo it cannot MES-3 activity, an essential PRC2 component in C. elegans, were mated; the embryonic chromatin patterns observed by Gaydos et al., (2014) are indithree maternal effect sterility reestablish H3K27me3 where cated. (A) Sperm chromatin with H3K27me3 retain this modification through (MES) proteins: MES-2 it doesn’t already exist. early divisions in embryos lacking PRC2; the mark is eventually lost though (EZH2), MES-6 (EED), and a Importantly, H3K27me3 was later divisions. (B) Sperm lacking H3K27me3 do not acquire it in the embryonic subunit specific to worms, observed to return to all germline, despite the presence of PRC2, but slowly accumulate it in larval germ cells. Note that there is no appreciable loss of H3K27me3 in the MES-3; all are required for chromosomes in activated oocyte-derived chromatin, indicating that PRC2 can maintain the levels of H3K27 methylation. Mutapostembryonic germ cells, this modification in the embryonic germline, but only in chromatin where it tions in all mes genes cause implying that PRC2 can propreexists. strict maternal effect sterility, vide de novo H3K27me3 after meaning that PRC2’s epigeactivation of zygotic trannetic activity in the parental germline is the sperm-donated chromosomes were scription in the germline. It is unclear why essential for germline development in brightly decorated by antibodies against the larval accumulation of H3K27me3 the offspring. The necessity of maternal H3K27me3, but the chromosomes does not occur in the embryonic germ PRC2 for provision of embryonic contributed by the oocytes were not. cells, where the PRC2 complex is enH3K27me3 provides an ideal situation Importantly, this pattern remained intact riched. The consequent establishment of for addressing the issue of whether during early cell divisions, and maternal this histone mark may be guided by a epigenetic inheritance is mediated by and paternal chromatin remained visually product produced by zygotic transcripthe chromatin modifiers or by the modifi- distinct, with the original pattern of pres- tion, which is significantly repressed in cations themselves. ence or absence of H3K27me3 persisting the embryonic germline in worms. The contrast between the results reGaydos and colleagues tested whether despite a considerable number of cell sperm chromatin, which carries sub- divisions. Although low resolution, these ported in flies and worms is striking: flies stantial H3K27me3, retains this mark results indicate that significant levels of appear to rely on sequence-directed reduring early cell divisions after fertilizing H3K27me3 can survive replication cycles establishment of H3K27me3 after replicaan oocyte lacking maternal PRC2 in the absence of PRC2 activity, demon- tion, whereas worms require transmission of the mark itself for its proper mainteactivity (Figure 1A). The two parental strating that the mark itself is heritable. chromosome sets showed strikingly They next addressed the reciprocal nance. PRC2 recruitment in mammals different chromatin patterns in the zygote: question: can paternal sperm chromatin is also guided by, among numerous Developmental Cell 31, October 27, 2014 ª2014 Elsevier Inc. 143
Developmental Cell
Previews proposed mechanisms, contributions from DNA sequence, and it displays a bias toward CpG islands (Margueron and Reinberg, 2011). Yet in both flies and mammals, the simple absence of transcription can also recruit PRC2 and H3K27me3 enrichment, and this may not always involve DNA sequence (Riising et al., 2014). In adult worm germ cells, the H3K36me3 mark is deposited as a consequence of germline transcription, and this epigenetic mark is maintained in the embryo by another MES protein, MES-4. This mark can indirectly guide H3K27me3 deposition through what appears to be mutual antagonism (Gaydos et al., 2012; reviewed in Kelly, 2014).
Germline transcription, or lack thereof, thus seems to provide much of the basis of epigenetic memory establishment in worms, and, as the work from Gaydos et al. (2014) shows, differential chromatin marks are necessary and sufficient for this memory. It is thus clear that a unified theory of epigenetic inheritance still escapes us, as we are once again reminded that life tends to paint different pictures in different species from a common palette. REFERENCES Campos, E.I., Stafford, J.M., and Reinberg, D. (2014). Trends Cell Biol. 24, in press. Published online September 18, 2014. http://dx.doi.org/10. 1016/j.tcb.2014.08.004.
144 Developmental Cell 31, October 27, 2014 ª2014 Elsevier Inc.
Gaydos, L.J., Rechtsteiner, A., Egelhofer, T.A., Carroll, C.R., and Strome, S. (2012). Cell Rep 2, 1169–1177. Gaydos, L.J., Wang, W., and Strome, S. (2014). Science 345, 1515–1518. Kelly, W.G. (2014). Epigenetics Chromatin 7, 6. Margueron, R., and Reinberg, D. (2011). Nature 469, 343–349. Petruk, S., Sedkov, Y., Johnston, D.M., Hodgson, J.W., Black, K.L., Kovermann, S.K., Beck, S., Canaani, E., Brock, H.W., and Mazo, A. (2012). Cell 150, 922–933. Riising, E.M., Comet, I., Leblanc, B., Wu, X., Johansen, J.V., and Helin, K. (2014). Mol. Cell 55, 347–360.
Previews and/or glomerular ultrafiltration due to loss of specialized podocyte foot processes (Doyonnas et al., 2001). By contrast, endothelial tubulogenesis and lumen formation were normal in these animals (Doyonnas et al., 2001), despite the fact that podocalyxin is apically expressed in ECs (Dekan et al., 1990). Although it is clear that epithelial and endothelial tubulogenic mechanisms have similar features, these cell types are functionally different. The mechanisms controlling apical-basal polarization in these cells, while similar, also have distinct features (Datta et al., 2011; Davis et al., 2011; Sacharidou et al., 2012). In contrast to epithelial polarization, EC polarization depends on unique signals derived from blood flow and shear stress on the EC apical surface, the vascular basement membrane com-
posed of different laminin isoforms (compared to epithelial basement membranes), and the close association of mural cells along the basal surface (Davis et al., 2011; Sacharidou et al., 2012). Together, these studies demonstrate common themes in both epithelial and endothelial systems as to how molecular switches control cell polarization. Bryant et al. (2014) provide a key lesson for future studies using different cell types and model systems by demonstrating that detailed molecular studies are necessary to elucidate the underlying basis for complex morphogenic processes, including lumen and tube formation.
Bryant, D.M., Datta, A., Rodrı´guez-Fraticelli, A.E., Pera¨nen, J., Martı´n-Belmonte, F., and Mostov, K.E. (2010). Nat. Cell Biol. 12, 1035–1045. Bryant, D.M., Roignot, J., Datta, A., Overeem, A.W., Kim, M., Yu, W., Peng, X., Eastburn, D.J., Ewald, A.J., Werb, Z., and Mostov, K.E. (2014). Dev. Cell, in press. Published online October 8, 2014. Datta, A., Bryant, D.M., and Mostov, K.E. (2011). Curr. Biol. 21, R126–R136. Davis, G.E., Stratman, A.N., Sacharidou, A., and Koh, W. (2011). Int Rev Cell Mol Biol 288, 101–165. Dekan, G., Miettinen, A., Schnabel, E., and Farquhar, M.G. (1990). Am. J. Pathol. 137, 913–927. Doyonnas, R., Kershaw, D.B., Duhme, C., Merkens, H., Chelliah, S., Graf, T., and McNagny, K.M. (2001). J. Exp. Med. 194, 13–27.
REFERENCES
Sacharidou, A., Stratman, A.N., and Davis, G.E. (2012). Cells Tissues Organs (Print) 195, 122–143.
Bryant, D.M., and Mostov, K.E. (2008). Nat. Rev. Mol. Cell Biol. 9, 887–901.
Xu, K., Sacharidou, A., Fu, S., Chong, D.C., Skaug, B., Chen, Z.J., Davis, G.E., and Cleaver, O. (2011). Dev. Cell 20, 526–539.
Multigenerational Chromatin Marks: No Enzymes Need Apply William G. Kelly1,* 1Biology Department, Emory University, Atlanta, GA 30322, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2014.10.008
Epigenetic memory stably maintains and transmits information during genome replication. Recently in Science, Gaydos et al. (2014) show that repressive chromatin marks exhibit transgenerational stability in the absence of chromatin-modifying enzymes in Caenorhabditis elegans, in contrast to work in flies suggesting that such proteins mediate stable inheritance of epigenetic modifications. Epigenetic processes drive heritable alterations in gene expression independently of changes in DNA sequences. While changes in gene expression always occur in cells in response to alterations in their environment, epigenetic heritability requires that these changes (which can be activating or repressive) are stable during and after cell division and that they no longer requires the factor(s) that initiated the change. A classic example is the maintenance of Hox gene expression patterns in fly embryos after the initiating transcription factors are no longer present. The conserved PcG enzyme E(z) or EZH2 adds methyl
groups to histone H3 on lysine 27 (H3K27me), and trimethylation of this residue (H3K27me3) is strongly correlated with gene repression in many organisms. E(z) acts in a conserved complex, called PRC2, along with Esc/EED; EED can bind H3K27me3 and recruit the complex to its own mark in a feedforward loop: PRC2 is recruited to nucleosomes with preexisting H3K27me3 to maintain or increase its regional enrichment (Margueron and Reinberg, 2011). Recent work in C. elegans from the group of Susan Strome now provides further insight into the mechanisms underlying PRC2/H3K27me3-mediated trans-
142 Developmental Cell 31, October 27, 2014 ª2014 Elsevier Inc.
mission of epigenetic memory (Gaydos et al., 2014). The contribution of modified histones to epigenetic memory has been debated because DNA replication involves massive dilution of chromatin-associated proteins and, possibly, extensive replacement of parental histones (reviewed in Campos et al., 2014). How might any histone-based information be faithfully transferred between cell divisions, let alone between generations, in the face of such histone dynamics? One possibility is that histonemodifying complexes, rather than the histone marks themselves, are anchored to target loci. This mechanism is supported
Developmental Cell
Previews by a study in Drosophila depleted of H3K27me3 that indicated that histonebecome marked by PRC2 de modifying activities including novo in the embryo? To test PRC2, and not the modificathis, they mated males lacking tions they produce, remained PRC2 activity, and therefore associated with the daughter lacking H3K27me3 in their DNA and subsequently reessperm, to hermaphrodites tablished the marks after repliwith normal PRC2 activity cation (Petruk et al., 2012). (Figure 1B). The offspring The mechanism presumably had maternally provided relies on DNA sequence inforPRC2 activity and had also mation to provide the anchor, inherited a functional gene rather than preexisting hisfrom the oocyte. As expected, tones; in flies, this information the maternal chromosomes is provided by Polycomb were brightly decorated with response elements (PREs). H3K27me in the zygote, but The new study from Gaydos the male chromosomes were et al. (2014), however, indinot. Despite the presence of cates that in C. elegans subPRC2, however, the spermstantial H3K27me3 can derived chromosomes had remain in the daughter chrono detectable accumulation matin after replication. of H3K27me3, at least in the Furthermore, preexisting germline, for the rest of H3K27me3 is required to embryogenesis. In contrast, maintain epigenetic memory no dilution of H3K27me3 was in the germline, indicating observed in the oocytethat histone modifications derived chromatin. This is can indeed provide a heritable strong evidence that in memory not only though cell C. elegans embryos the divisions, but also across PRC2 complex maintains Figure 1. H3K27me3 Persistence and Pattern Maintenance in generations. preexisting H3K27me3 estabC. elegans Embryos and Germline The C. elegans PRC2 lished in the parental germline Gametes originating from germlines with (green-filled) or without (red-filled) complex is composed of but in the embryo it cannot MES-3 activity, an essential PRC2 component in C. elegans, were mated; the embryonic chromatin patterns observed by Gaydos et al., (2014) are indithree maternal effect sterility reestablish H3K27me3 where cated. (A) Sperm chromatin with H3K27me3 retain this modification through (MES) proteins: MES-2 it doesn’t already exist. early divisions in embryos lacking PRC2; the mark is eventually lost though (EZH2), MES-6 (EED), and a Importantly, H3K27me3 was later divisions. (B) Sperm lacking H3K27me3 do not acquire it in the embryonic subunit specific to worms, observed to return to all germline, despite the presence of PRC2, but slowly accumulate it in larval germ cells. Note that there is no appreciable loss of H3K27me3 in the MES-3; all are required for chromosomes in activated oocyte-derived chromatin, indicating that PRC2 can maintain the levels of H3K27 methylation. Mutapostembryonic germ cells, this modification in the embryonic germline, but only in chromatin where it tions in all mes genes cause implying that PRC2 can propreexists. strict maternal effect sterility, vide de novo H3K27me3 after meaning that PRC2’s epigeactivation of zygotic trannetic activity in the parental germline is the sperm-donated chromosomes were scription in the germline. It is unclear why essential for germline development in brightly decorated by antibodies against the larval accumulation of H3K27me3 the offspring. The necessity of maternal H3K27me3, but the chromosomes does not occur in the embryonic germ PRC2 for provision of embryonic contributed by the oocytes were not. cells, where the PRC2 complex is enH3K27me3 provides an ideal situation Importantly, this pattern remained intact riched. The consequent establishment of for addressing the issue of whether during early cell divisions, and maternal this histone mark may be guided by a epigenetic inheritance is mediated by and paternal chromatin remained visually product produced by zygotic transcripthe chromatin modifiers or by the modifi- distinct, with the original pattern of pres- tion, which is significantly repressed in cations themselves. ence or absence of H3K27me3 persisting the embryonic germline in worms. The contrast between the results reGaydos and colleagues tested whether despite a considerable number of cell sperm chromatin, which carries sub- divisions. Although low resolution, these ported in flies and worms is striking: flies stantial H3K27me3, retains this mark results indicate that significant levels of appear to rely on sequence-directed reduring early cell divisions after fertilizing H3K27me3 can survive replication cycles establishment of H3K27me3 after replicaan oocyte lacking maternal PRC2 in the absence of PRC2 activity, demon- tion, whereas worms require transmission of the mark itself for its proper mainteactivity (Figure 1A). The two parental strating that the mark itself is heritable. chromosome sets showed strikingly They next addressed the reciprocal nance. PRC2 recruitment in mammals different chromatin patterns in the zygote: question: can paternal sperm chromatin is also guided by, among numerous Developmental Cell 31, October 27, 2014 ª2014 Elsevier Inc. 143
Developmental Cell
Previews proposed mechanisms, contributions from DNA sequence, and it displays a bias toward CpG islands (Margueron and Reinberg, 2011). Yet in both flies and mammals, the simple absence of transcription can also recruit PRC2 and H3K27me3 enrichment, and this may not always involve DNA sequence (Riising et al., 2014). In adult worm germ cells, the H3K36me3 mark is deposited as a consequence of germline transcription, and this epigenetic mark is maintained in the embryo by another MES protein, MES-4. This mark can indirectly guide H3K27me3 deposition through what appears to be mutual antagonism (Gaydos et al., 2012; reviewed in Kelly, 2014).
Germline transcription, or lack thereof, thus seems to provide much of the basis of epigenetic memory establishment in worms, and, as the work from Gaydos et al. (2014) shows, differential chromatin marks are necessary and sufficient for this memory. It is thus clear that a unified theory of epigenetic inheritance still escapes us, as we are once again reminded that life tends to paint different pictures in different species from a common palette. REFERENCES Campos, E.I., Stafford, J.M., and Reinberg, D. (2014). Trends Cell Biol. 24, in press. Published online September 18, 2014. http://dx.doi.org/10. 1016/j.tcb.2014.08.004.
144 Developmental Cell 31, October 27, 2014 ª2014 Elsevier Inc.
Gaydos, L.J., Rechtsteiner, A., Egelhofer, T.A., Carroll, C.R., and Strome, S. (2012). Cell Rep 2, 1169–1177. Gaydos, L.J., Wang, W., and Strome, S. (2014). Science 345, 1515–1518. Kelly, W.G. (2014). Epigenetics Chromatin 7, 6. Margueron, R., and Reinberg, D. (2011). Nature 469, 343–349. Petruk, S., Sedkov, Y., Johnston, D.M., Hodgson, J.W., Black, K.L., Kovermann, S.K., Beck, S., Canaani, E., Brock, H.W., and Mazo, A. (2012). Cell 150, 922–933. Riising, E.M., Comet, I., Leblanc, B., Wu, X., Johansen, J.V., and Helin, K. (2014). Mol. Cell 55, 347–360.
