Key Points
-
The genome remains mostly constant during development and ageing.
-
Cells differ in which part of the genome they express. The gene-expression programme is determined by the presence of transcriptional regulators.
-
The cloning of various organisms from different cell types shows that the differentiated state and cellular changes that occur during ageing are reversible. This reversion is referred to as reprogramming.
-
Transcriptional regulators dissociate from the chromatin during cell division. The transcriptional programme, and with it a cellular state, is newly established after every cell division, thereby challenging the old state as well as providing the opportunity to transit to another state.
-
Exposing a genome to a different set of transcriptional regulators can change its gene-expression programme and with it cellular identity. This can be done by ectopic expression of transcription factors, cell fusion or nuclear transfer.
-
Transfer of a somatic cell genome into an unfertilized oocyte or a zygote in mitosis allows the derivation of pluripotent embryonic stem-cell lines from the cloned preimplantation stage embryos.
-
Fusion of a somatic cell with an embryonic stem cell can reprogramme the somatic cell genome to an embryonic state.
-
The ectopic expression of a combination of embryonic stem-cell transcription factors can reprogramme a somatic cell to an embryonic state.
Abstract
It is thought that most cell types of the human body share the same genetic information as that contained in the zygote from which they originate. Consistent with this view, animal cloning studies demonstrated that the intact genome of a differentiated cell can be reprogrammed to support the development of an entire organism and allow the production of pluripotent stem cells. Recent progress in reprogramming research now points to an important role for transcription factors in the establishment and the maintenance of cellular phenotypes, and to cell division as a mediator of transitions between different states of gene expression.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Briggs, R. & King, T. J. Transplantation of living nuclei from blastula cells into enucleated frogs' eggs. Proc. Natl Acad. Sci. USA 38, 455–463 (1952).
Gurdon, J. B., Elsdale, T. R. & Fischberg, M. Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei. Nature 182, 64–65 (1958). Demonstrates that frogs can be cloned from somatic cells.
Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J. & Campbell, K. H. Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813 (1997). Demonstrates the reversibility of mammalian differentiation.
Eggan, K. et al. Mice cloned from olfactory sensory neurons. Nature 428, 44–49 (2004).
Hochedlinger, K. & Jaenisch, R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 415, 1035–1038 (2002). Demonstrates that the genome of even the most differentiated cells can support development after nuclear transfer.
Inoue, K. et al. Generation of cloned mice by direct nuclear transfer from natural killer T cells. Curr. Biol. 15, 1114–1118 (2005).
Brambrink, T., Hochedlinger, K., Bell, G. & Jaenisch, R. ES cells derived from cloned and fertilized blastocysts are transcriptionally and functionally indistinguishable. Proc. Natl Acad. Sci. USA 103, 933–938 (2006).
Beyhan, Z. et al. Transcriptional reprogramming of somatic cell nuclei during preimplantation development of cloned bovine embryos. Dev. Biol. 305, 637–649 (2007).
Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).
Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet. 33 245–254 (2003).
Santos, F., Hendrich, B., Reik, W. & Dean, W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev. Biol. 241, 172–182 (2002).
Dean, W. et al. Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proc. Natl Acad. Sci. USA 98, 13734–13738 (2001).
Santos, F. et al. Epigenetic marking correlates with developmental potential in cloned bovine preimplantation embryos. Curr. Biol. 13, 1116–1121 (2003).
Rideout, W. M., Eggan, K. & Jaenisch, R. Nuclear cloning and epigenetic reprogramming of the genome. Science 293, 1093–1098 (2001).
Morgan, H. D., Santos, F., Green, K., Dean, W. & Reik, W. Epigenetic reprogramming in mammals. Hum. Mol. Genet. 14 R47–R58 (2005).
Simonsson, S. & Gurdon, J. B. Changing cell fate by nuclear reprogramming. Cell Cycle 4, 513–515 (2005).
Reik, W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425–432 (2007).
Holliday, R. The inheritance of epigenetic defects. Science 238, 163–170 (1987).
Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).
Chesne, P. et al. Cloned rabbits produced by nuclear transfer from adult somatic cells. Nature Biotechnol. 20, 366–369 (2002).
Wakayama, T., Perry, A. C., Zuccotti, M., Johnson, K. R. & Yanagimachi, R. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394, 369–374 (1998).
Mitalipov, S. M. et al. Reprogramming following somatic cell nuclear transfer in primates is dependent upon nuclear remodeling. Hum. Reprod. 22, 2232–2242 (2007).
Wakayama, T., Tateno, H., Mombaerts, P. & Yanagimachi, R. Nuclear transfer into mouse zygotes. Nature Genet. 24, 108–109 (2000).
DiBerardino, M. A. Nuclear and chromosomal behavior in amphibian nuclear transplants. Int. Rev. Cytol. Suppl. 129–160 (1979).
Egli, D., Rosains, J., Birkhoff, G. & Eggan, K. Developmental reprogramming after chromosome transfer into mitotic mouse zygotes. Nature 447, 679–685 (2007). Demonstrates that a genome can be exchanged during mitosis, resulting in developmental reprogramming.
Lemaitre, J. M., Danis, E., Pasero, P., Vassetzky, Y. & Mechali, M. Mitotic remodeling of the replicon and chromosome structure. Cell 123, 787–801 (2005). Shows that chromosome condensation is required to reprogramme the position of origins of replication.
Natale, D. A., Li, C. J., Sun, W. H. & DePamphilis, M. L. Selective instability of Orc1 protein accounts for the absence of functional origin recognition complexes during the M–G1 transition in mammals. EMBO J. 19, 2728–2738 (2000).
Wu, J. R. & Gilbert, D. M. A distinct G1 step required to specify the Chinese hamster DHFR replication origin. Science 271, 1270–1272 (1996).
Cuvier, O., Stanojcic, S., Lemaitre, J. M. & Mechali, M. A topoisomerase II-dependent mechanism for resetting replicons at the S–M-phase transition. Genes Dev. 22, 860–865 (2008).
Romanowski, P., Madine, M. A., Rowles, A., Blow, J. J. & Laskey, R. A. The Xenopus origin recognition complex is essential for DNA replication and MCM binding to chromatin. Curr. Biol. 6, 1416–1425 (1996).
McGrath, J. & Solter, D. Nuclear transplantation in the mouse embryo by microsurgery and cell fusion. Science 220, 1300–1302 (1983).
Modlinski, J. A. & Smorag, Z. Preimplantation development of rabbit embryos after transfer of embryonic nuclei into different cytoplasmic environment. Mol. Reprod. Dev. 28, 361–372 (1991).
Robl, J. M., Gilligan, B., Critser, E. S. & First, N. L. Nuclear transplantation in mouse embryos: assessment of recipient cell stage. Biol. Reprod. 34, 733–739 (1986).
McGrath, J. & Solter, D. Inability of mouse blastomere nuclei transferred to enucleated zygotes to support development in vitro. Science 226, 1317–1319 (1984). Demonstrates that the exchange of nuclei between different cell types in interphase does not result in developmental reprogramming.
Cheong, H. T. & Kanagawa, H. Assessment of cytoplasmic effects on the development of mouse embryonic nuclei transferred to enucleated zygotes. Theriogenology 39, 451–461 (1993).
Tsunoda, Y. et al. Full-term development of mouse blastomere nuclei transplanted into enucleated two-cell embryos. J. Exp. Zool. 242, 147–151 (1987).
Kono, T. & Tsunoda, Y. Development of single blastomeres from four- and eight-cell mouse embryos fused into the enucleated half of a two-cell embryo. Gamete Res. 22, 427–434 (1989).
Willadsen, S. M. Nuclear transplantation in sheep embryos. Nature 320, 63–65 (1986).
Gao, S. et al. Germinal vesicle material is essential for nucleus remodeling after nuclear transfer. Biol. Reprod. 67, 928–934 (2002).
Prescott, D. M. & Bender, M. A. Synthesis of RNA and protein during mitosis in mammalian tissue culture cells. Exp. Cell Res. 26, 260–268 (1962).
Taylor, J. H. Nucleic acid synthesis in relation to the cell division cycle. Ann. N. Y Acad. Sci. 90, 409–421 (1960).
Littau, V. C., Allfrey, V. G., Frenster, J. H. & Mirsky, A. E. Active and inactive regions of nuclear chromatin as revealed by electron microscope autoradiography. Proc. Natl Acad. Sci. USA 52, 93–100 (1964).
Johnson, T. C. & Holland, J. J. Ribonucleic acid and protein synthesis in mitotic HeLa cells. J. Cell Biol. 27, 565–574 (1965).
Bouniol-Baly, C. et al. Differential transcriptional activity associated with chromatin configuration in fully grown mouse germinal vesicle oocytes. Biol. Reprod. 60, 580–587 (1999).
Gottesfeld, J. M. & Forbes, D. J. Mitotic repression of the transcriptional machinery. Trends Biochem. Sci. 22, 197–202 (1997).
Sun, F. et al. Nuclear reprogramming: the zygotic transcription program is established through an “erase-and-rebuild” strategy. Cell Res. 17, 117–134 (2007).
Martinez-Balbas, M. A., Dey, A., Rabindran, S. K., Ozato, K. & Wu, C. Displacement of sequence-specific transcription factors from mitotic chromatin. Cell 83, 29–38 (1995). Describes the extensive dissociation of transcriptional regulators from the DNA during mitosis.
Hershkovitz, M. & Riggs, A. D. Metaphase chromosome analysis by ligation-mediated PCR: heritable chromatin structure and a comparison of active and inactive X chromosomes. Proc. Natl Acad. Sci. USA 92, 2379–2383 (1995).
Komura, J. & Ono, T. Disappearance of nucleosome positioning in mitotic chromatin in vivo. J. Biol. Chem. 280, 14530–14535 (2005).
Boyd, D. C., Pombo, A. & Murphy, S. Interaction of proteins with promoter elements of the human U2 snRNA genes in vivo. Gene 315, 103–112 (2003).
Muchardt, C., Reyes, J. C., Bourachot, B., Leguoy, E. & Yaniv, M. The hbrm and BRG-1 proteins, components of the human SNF/SWI complex, are phosphorylated and excluded from the condensed chromosomes during mitosis. EMBO J. 15, 3394–3402 (1996).
Sif, S., Stukenberg, P. T., Kirschner, M. W. & Kingston, R. E. Mitotic inactivation of a human SWI/SNF chromatin remodeling complex. Genes Dev. 12, 2842–2851 (1998).
Schild, C., Claret, F. X., Wahli, W. & Wolffe, A. P. A nucleosome-dependent static loop potentiates estrogen-regulated transcription from the Xenopus vitellogenin B1 promoter in vitro. EMBO J. 12, 423–433 (1993).
Buchenau, P., Hodgson, J., Strutt, H. & Arndt-Jovin, D. J. The distribution of polycomb-group proteins during cell division and development in Drosophila embryos: impact on models for silencing. J. Cell Biol. 141, 469–481 (1998).
Voncken, J. W. et al. Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status. J. Cell Sci. 112, 4627–4639 (1999).
Miyagishima, H. et al. Dissociation of mammalian Polycomb-group proteins, Ring1B and Rae28/Ph1, from the chromatin correlates with configuration changes of the chromatin in mitotic and meiotic prophase. Histochem. Cell Biol. 120, 111–119 (2003).
Saurin, A. J. et al. The human polycomb group complex associates with pericentromeric heterochromatin to form a novel nuclear domain. J. Cell Biol. 142, 887–898 (1998).
Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).
Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).
Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).
Kellum, R., Raff, J. W. & Alberts, B. M. Heterochromatin protein 1 distribution during development and during the cell cycle in Drosophila embryos. J. Cell Sci. 108, 1407–1418 (1995).
Minc, E., Allory, Y., Worman, H. J., Courvalin, J. C. & Buendia, B. Localization and phosphorylation of HP1 proteins during the cell cycle in mammalian cells. Chromosoma 108, 220–234 (1999).
Terada, Y. Aurora-B/AIM-1 regulates the dynamic behavior of HP1α at the G2–M transition. Mol. Biol. Cell 17, 3232–3241 (2006).
Sugimoto, K., Tasaka, H. & Dotsu, M. Molecular behavior in living mitotic cells of human centromere heterochromatin protein HPLα ectopically expressed as a fusion to red fluorescent protein. Cell Struct. Funct. 26, 705–718 (2001).
Murzina, N., Verreault, A., Laue, E. & Stillman, B. Heterochromatin dynamics in mouse cells: interaction between chromatin assembly factor 1 and HP1 proteins. Mol. Cell 4, 529–540 (1999).
Hayakawa, T., Haraguchi, T., Masumoto, H. & Hiraoka, Y. Cell cycle behavior of human HP1 subtypes: distinct molecular domains of HP1 are required for their centromeric localization during interphase and metaphase. J. Cell Sci. 116, 3327–3338 (2003).
Hsu, J. Y. et al. Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 102, 279–291 (2000).
Fischle, W. et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438, 1116–1122 (2005).
Hirota, T., Lipp, J. J., Toh, B. H. & Peters, J. M. Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature 438, 1176–1180 (2005). REFS 70 and 71 describe the mechanism that leads to the dissociation of HP1 from mitotic chromatin.
Mateescu, B., England, P., Halgand, F., Yaniv, M. & Muchardt, C. Tethering of HP1 proteins to chromatin is relieved by phosphoacetylation of histone H3. EMBO Rep. 5, 490–496 (2004).
Peters, A. H. et al. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nature Genet. 30, 77–80 (2002).
Aagaard, L., Schmid, M., Warburton, P. & Jenuwein, T. Mitotic phosphorylation of SUV39H1, a novel component of active centromeres, coincides with transient accumulation at mammalian centromeres. J. Cell Sci. 113, 817–829 (2000).
Stein, R., Gruenbaum, Y., Pollack, Y., Razin, A. & Cedar, H. Clonal inheritance of the pattern of DNA methylation in mouse cells. Proc. Natl Acad. Sci. USA 79, 61–65 (1982).
Nan, X., Campoy, F. J. & Bird, A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88, 471–481 (1997).
Ng, H. H., Jeppesen, P. & Bird, A. Active repression of methylated genes by the chromosomal protein MBD1. Mol. Cell Biol. 20, 1394–1406 (2000).
Ahmad, K. & Henikoff, S. The histone variant H3.3 marks active chromatin by replication-independent nucleosome assembly. Mol. Cell 9, 1191–1200 (2002).
Kuo, M. T., Iyer, B. & Schwarz, R. J. Condensation of chromatin into chromosomes preserves an open configuration but alters the DNase I hypersensitive cleavage sites of the transcribed gene. Nucleic Acids Res. 10, 4565–4579 (1982).
Sarge, K. D. & Park-Sarge, O. K. Gene bookmarking: keeping the pages open. Trends Biochem. Sci. 30, 605–610 (2005).
John, S. & Workman, J. L. Bookmarking genes for activation in condensed mitotic chromosomes. Bioessays 20, 275–279 (1998).
Plath, K. et al. Developmentally regulated alterations in Polycomb repressive complex 1 proteins on the inactive X chromosome. J. Cell Biol. 167, 1025–1035 (2004).
Mak, W. et al. Mitotically stable association of polycomb group proteins eed and enx1 with the inactive x chromosome in trophoblast stem cells. Curr. Biol. 12, 1016–1020 (2002).
Allshire, R. C., Nimmo, E. R., Ekwall, K., Javerzat, J. P. & Cranston, G. Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation. Genes Dev. 9, 218–233 (1995).
Ekwall, K. et al. Mutations in the fission yeast silencing factors clr4+ and rik1+ disrupt the localisation of the chromo domain protein Swi6p and impair centromere function. J. Cell Sci. 109, 2637–2648 (1996).
Bhat, K. M. et al. The GAGA factor is required in the early Drosophila embryo not only for transcriptional regulation but also for nuclear division. Development 122, 1113–1124 (1996).
Platero, J. S., Csink, A. K., Quintanilla, A. & Henikoff, S. Changes in chromosomal localization of heterochromatin-binding proteins during the cell cycle in Drosophila. J. Cell Biol. 140, 1297–1306 (1998).
Raff, J. W., Kellum, R. & Alberts, B. The Drosophila GAGA transcription factor is associated with specific regions of heterochromatin throughout the cell cycle. EMBO J. 13, 5977–5983 (1994).
Chen, D., Hinkley, C. S., Henry, R. W. & Huang, S. TBP dynamics in living human cells: constitutive association of TBP with mitotic chromosomes. Mol. Biol. Cell 13, 276–284 (2002).
Christova, R. & Oelgeschlager, T. Association of human TFIID-promoter complexes with silenced mitotic chromatin in vivo. Nature Cell Biol. 4, 79–82 (2002).
Segil, N., Guermah, M., Hoffmann, A., Roeder, R. G. & Heintz, N. Mitotic regulation of TFIID: inhibition of activator-dependent transcription and changes in subcellular localization. Genes Dev. 10, 2389–2400 (1996).
Lanctot, C., Cheutin, T., Cremer, M., Cavalli, G. & Cremer, T. Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nature Rev. Genet. 8, 104–115 (2007).
Bolzer, A. et al. Three-dimensional maps of all chromosomes in human male fibroblast nuclei and prometaphase rosettes. PLoS Biol. 3, e157 (2005).
Iborra, F. J., Pombo, A., Jackson, D. A. & Cook, P. R. Active RNA polymerases are localized within discrete transcription 'factories' in human nuclei. J. Cell Sci. 109, 1427–1436 (1996).
Chubb, J. R., Boyle, S., Perry, P. & Bickmore, W. A. Chromatin motion is constrained by association with nuclear compartments in human cells. Curr. Biol. 12, 439–445 (2002).
Walter, J., Schermelleh, L., Cremer, M., Tashiro, S. & Cremer, T. Chromosome order in HeLa cells changes during mitosis and early G1, but is stably maintained during subsequent interphase stages. J. Cell Biol. 160, 685–697 (2003).
Reddy, K. L., Zullo, J. M., Bertolino, E. & Singh, H. Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature 452, 243–247 (2008). Demonstrates that mitosis can mediate repositioning of a locus within the nucleus, resulting in a change in the state of gene expression.
Kosak, S. T. et al. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296, 158–162 (2002).
Tumbar, T. & Belmont, A. S. Interphase movements of a DNA chromosome region modulated by VP16 transcriptional activator. Nature Cell Biol. 3, 134–139 (2001).
Goldman, R. D. et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 101, 8963–8968 (2004).
Scaffidi, P. & Misteli, T. Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Nature Cell Biol. 10, 452–459 (2008).
Knoblich, J. A. Asymmetric cell division during animal development. Nature Rev. Mol. Cell Biol. 2, 11–20 (2001).
Gonczy, P. Mechanisms of asymmetric cell division: flies and worms pave the way. Nature Rev. Mol. Cell Biol. 9, 355–366 (2008).
Shao, Z. et al. Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 98, 37–46 (1999).
King, I. F., Francis, N. J. & Kingston, R. E. Native and recombinant polycomb group complexes establish a selective block to template accessibility to repress transcription in vitro. Mol. Cell Biol. 22, 7919–7928 (2002).
Zink, D. & Paro, R. Drosophila Polycomb-group regulated chromatin inhibits the accessibility of a trans-activator to its target DNA. EMBO J. 14, 5660–5671 (1995).
Eggan, K. et al. Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc. Natl Acad. Sci. USA 98, 6209–6214 (2001).
Humpherys, D. et al. Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus cell nuclei. Proc. Natl Acad. Sci. USA 99, 12889–12894 (2002).
Boiani, M., Eckardt, S., Scholer, H. R. & McLaughlin, K. J. Oct4 distribution and level in mouse clones: consequences for pluripotency. Genes Dev. 16, 1209–1219 (2002).
Blelloch, R. et al. Reprogramming efficiency following somatic cell nuclear transfer is influenced by the differentiation and methylation state of the donor nucleus. Stem Cells 24, 2007–2013 (2006).
Kishigami, S. et al. Significant improvement of mouse cloning technique by treatment with trichostatin A after somatic nuclear transfer. Biochem. Biophys. Res. Commun. 340, 183–189 (2006).
Rybouchkin, A., Kato, Y. & Tsunoda, Y. Role of histone acetylation in reprogramming of somatic nuclei following nuclear transfer. Biol. Reprod. 74, 1083–1089 (2006).
Gurdon, J. B. & Colman, A. The future of cloning. Nature 402, 743–746 (1999).
Lanza, R. P., Cibelli, J. B. & West, M. D. Human therapeutic cloning. Nature Med. 5, 975–977 (1999).
Niwa, H., Miyazaki, J. & Smith, A. G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nature Genet. 24, 372–376 (2000).
Masui, S. et al. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nature Cell Biol. 9, 625–635 (2007).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). The forced expression of embryonic transcription factors can change the transcriptional programme and the developmental potential from somatic to embryonic.
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007). A milestone in cellular reprogramming: human pluripotent stem cells can be generated just like in the mouse (see Ref. 117).
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Park, I. H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).
Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).
Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 160–162 (2007).
Maherali, N. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55–70 (2007).
Hanna, J. et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133, 250–264 (2008).
Cobaleda, C., Jochum, W. & Busslinger, M. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 449, 473–477 (2007). Shows that the differentiated state of B cells requires the presence of the transcription factor PAX5.
Weintraub, H. et al. Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc. Natl Acad. Sci. USA 86, 5434–5438 (1989). Shows that the ectopic expression of a transcription factor of a differentiated cell can lead to trans-differentiation.
Blau, H. M. et al. Plasticity of the differentiated state. Science 230, 758–766 (1985). Demonstrates the induction of muscle-gene expression after fusion of a non-muscle cell to a muscle cell.
De Robertis, E. M. & Gurdon, J. B. Gene activation in somatic nuclei after injection into amphibian oocytes. Proc. Natl Acad. Sci. USA 74, 2470–2474 (1977).
Kikyo, N., Wade, P. A., Guschin, D., Ge, H. & Wolffe, A. P. Active remodeling of somatic nuclei in egg cytoplasm by the nucleosomal ATPase ISWI. Science 289, 2360–2362 (2000).
Gurdon, J. B., Laskey, R. A. & Reeves, O. R. The developmental capacity of nuclei transplanted from keratinized skin cells of adult frogs. J. Embryol. Exp. Morphol. 34, 93–112 (1975).
Holtzer, H. et al. Lineages, quantal cell cycles, and the generation of cell diversity. Q. Rev. Biophys. 8, 523–557 (1975).
Pavlath, G. K. & Blau, H. M. Expression of muscle genes in heterokaryons depends on gene dosage. J. Cell Biol. 102, 124–130 (1986).
Cowan, C. A., Atienza, J., Melton, D. A. & Eggan, K. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309, 1369–1373 (2005). The first demonstration that the differentiated state of human cells can be reverted to an embryonic state.
Tada, M., Takahama, Y., Abe, K., Nakatsuji, N. & Tada, T. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr. Biol. 11, 1553–1558 (2001).
Jaenisch, R. & Young, R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132, 567–582 (2008).
Han, D. W. et al. Pluripotential reprogramming of the somatic genome in hybrid cells occurs with the first cell cycle. Stem Cells 26, 445–454 (2008).
Stadtfeld, M., Maherali, N., Breault, D. T. & Hochedlinger, K. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2, 230–240 (2008).
Brambrink, T. et al. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell 2, 151–159 (2008).
Feinberg, A. P. Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440 (2007).
Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007).
Lanza, R. P. et al. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 288, 665–669 (2000). Demonstrates that the process of ageing can be reverted after nuclear transfer into an unfertilized oocyte.
Bernstein, B. E., Meissner, A. & Lander, E. S. The mammalian epigenome. Cell 128, 669–681 (2007).
Henikoff, S. Nucleosome destabilization in the epigenetic regulation of gene expression. Nature Rev. Genet. 9, 15–26 (2008).
Costanzi, C. & Pehrson, J. R. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature 393, 599–601 (1998).
Bannister, A. J. & Kouzarides, T. Reversing histone methylation. Nature 436, 1103–1106 (2005).
Matsuo, K. et al. An embryonic demethylation mechanism involving binding of transcription factors to replicating DNA. EMBO J. 17, 1446–1453 (1998).
Kress, C., Thomassin, H. & Grange, T. Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks. Proc. Natl Acad. Sci. USA 103, 11112–11117 (2006).
Kangaspeska, S. et al. Transient cyclical methylation of promoter DNA. Nature 452, 112–115 (2008).
Metivier, R. et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature 452, 45–50 (2008).
Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).
Orlando, V. Polycomb, epigenomes, and control of cell identity. Cell 112, 599–606 (2003).
Schwartz, Y. B. & Pirrotta, V. Polycomb silencing mechanisms and the management of genomic programmes. Nature Rev. Genet. 8, 9–22 (2007).
Simon, J. A. & Tamkun, J. W. Programming off and on states in chromatin: mechanisms of Polycomb and trithorax group complexes. Curr. Opin. Genet. Dev. 12, 210–218 (2002).
Francis, N. J. & Kingston, R. E. Mechanisms of transcriptional memory. Nature Rev. Mol. Cell Biol. 2, 409–421 (2001).
Simon, J., Chiang, A. & Bender, W. Ten different Polycomb group genes are required for spatial control of the AbdA and AbdB homeotic products. Development 114, 493–505 (1992).
Juergens, G. A group of genes controlling the spatial expression of the bithorax complex in Drosophila. Nature 316, 153–155 (1985).
Fischle, W. et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev. 17, 1870–1881 (2003).
Poux, S., Horard, B., Sigrist, C. J. & Pirrotta, V. The Drosophila trithorax protein is a coactivator required to prevent re-establishment of polycomb silencing. Development 129, 2483–2493 (2002).
Klymenko, T. & Muller, J. The histone methyltransferases Trithorax and Ash1 prevent transcriptional silencing by Polycomb group proteins. EMBO Rep. 5, 373–377 (2004).
Wendt, K. S. et al. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature 451, 796–801 (2008).
Voncken, J. W. et al. MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1. J. Biol. Chem. 280, 5178–5187 (2005).
Wissmann, M. et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nature Cell Biol. 9, 347–353 (2007).
Yamane, K. et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483–495 (2006).
Agalioti, T. et al. Ordered recruitment of chromatin modifying and general transcription factors to the IFN-β promoter. Cell 103, 667–678 (2000).
Acknowledgements
D.E. thanks I. Tabansky, A. J. Tanaka, C. Fitzgerald, A. Chen, K. Rodolfa, R. Jiao, K. Niakan, S. Sullivan, A. Tajonar, E. Son and R. Maehr for comments on the manuscript. D.E. is supported by a Harvard Stem Cell Institute (USA) seed grant funded by the Singer family foundation. K.E. is a fellow of the John D. and Catherine T. MacArthur Foundation. We apologize for the many exciting studies that could not be included in this article because of space constraints.
Author information
Authors and Affiliations
Corresponding author
Supplementary information
41580_2008_BFnrm2439_MOESM1_ESM.pdf
Supplementary information S1 (table) | Factors with nuclear localization during interphase and dissociation from chromatin during mitosis or meiosis (PDF 246 kb)
Related links
Glossary
- Nuclear transfer
-
(NT). The transfer of a genome within an intact nucleus during interphase.
- Terminally differentiated cell
-
A cell that does not give rise to a cell type other than that of itself.
- Oocyte
-
An unfertilized egg.
- Reprogramming
-
An induced transition in cellular identity, usually meaning the reversal of differentiation.
- Cellular state
-
A cellular phenotype that includes developmental potential, the state of differentiation and functional specialization, replicative life-span and whether a cell is transformed to display aspects of disease.
- Zygote
-
A fertilized egg.
- Blastocyst
-
The embryo before implantation that contains at least two distinct cell types: the trophectoderm and the inner cell mass.
- Chromosome transfer
-
The transfer of a genome that is packaged in condensed chromosomes.
- Replication origin
-
A site where replication is initiated during S phase. It is bound by the origin of replication complex.
- M phase
-
Mitosis and meiosis.
- Topoisomerase II
-
(topo II). A protein that decatenates DNA in an ATP-dependent manner. It is also required for chromosome condensation.
- Cytoplast
-
A cell that does not contain a nuclear genome, but does contain mitochondria with genetic information.
- Embryonic stem cell
-
(ES). A pluripotent cell that can be derived from the inner cell mass of the blastocyst-stage embryo.
- Homeotic genes
-
Genes that encode homeodomain-containing transcription factors that are involved in the patterning of the body during development.
- Heterochromatin
-
DNA packed into a transcriptionally repressive chromatin structure.
- Pericentric heterochromatin
-
The heterochromatin of the chromosomal arms that is close to the centromeres.
- Euchromatin
-
A form of chromatin that is lightly packed and often transcriptionally active during interphase.
- Karyoplast
-
A nucleus or mitotic genome without the cytoplasm.
- Pluripotent stem cell
-
A cell that can give rise to cell types of the three germ layers — endoderm, mesoderm and ectoderm — and to germ cells.
- Cell fusion
-
The fusion of two or more cells resulting in a single, fused cell. This can be done by the application of an electric field or chemicals, such as polyethylene glycol.
Rights and permissions
About this article
Cite this article
Egli, D., Birkhoff, G. & Eggan, K. Mediators of reprogramming: transcription factors and transitions through mitosis. Nat Rev Mol Cell Biol 9, 505–516 (2008). https://doi.org/10.1038/nrm2439
Issue Date:
DOI: https://doi.org/10.1038/nrm2439
This article is cited by
-
Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin
Epigenetics & Chromatin (2023)
-
Parental competition for the regulators of chromatin dynamics in mouse zygotes
Communications Biology (2022)
-
Embryonic fate after somatic cell nuclear transfer in non-enucleated goldfish oocytes is determined by first cleavages and DNA methylation patterns
Scientific Reports (2021)
-
Gene expression and cell identity controlled by anaphase-promoting complex
Nature (2020)
-
Epigenetic regulation and mechanobiology
Biophysics Reports (2020)