Key Points
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Pluripotent stem cells use a complex network of genetic and epigenetic pathways to maintain a delicate balance between self-renewal and multilineage differentiation.
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Novel DNA demethylation pathways have been shown to be important in somatic cell reprogramming. Actively manipulating these pathways may enhance the efficiency of induced pluripotent stem (iPS) cell generation.
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Histone modifications are dynamically regulated during pluripotent stem cell differentiation. Recent studies identified mechanisms by which histone modifying proteins such as the Polycomb group (PcG) complex and Lys-specific demethylase 1 (LSD1) target different genes in the pluripotent and differentiated states.
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Chromatin-remodelling factors such as the BRG- or BRM-associated factor (BAF) complex and the nucleosome remodelling and deacetylase (NuRD) complex regulate transcription by modulating target gene chromatin accessibility. Chromatin remodellers often function cooperatively with other epigenetic regulators including histone- and DNA-modifying activities in pluripotent stem cells.
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High-resolution mapping of higher-order chromatin structure in embryonic stem (ES) cells and differentiated cells shows that the organization of the genome into topologically distinct domains is a fundamental feature of the mammalian genome.
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The maintenance of pluripotency and the initiation of differentiation involve an orchestrated change of the composition, localization and activity of various nuclear lamina components and require a highly dynamic interaction between the nuclear envelope and the genome.
Abstract
Pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, use a complex network of genetic and epigenetic pathways to maintain a delicate balance between self-renewal and multilineage differentiation. Recently developed high-throughput genomic tools greatly facilitate the study of epigenetic regulation in pluripotent stem cells. Increasing evidence suggests the existence of extensive crosstalk among epigenetic pathways that modify DNA, histones and nucleosomes. Novel methods of mapping higher-order chromatin structure and chromatin–nuclear matrix interactions also provide the first insight into the three-dimensional organization of the genome and a framework in which existing genomic data of epigenetic regulation can be integrated to discover new rules of gene regulation.
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References
Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Martin, G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634–7638 (1981).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (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).
Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).
Chen, T., Ueda, Y., Dodge, J. E., Wang, Z. & Li, E. Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol. Cell. Biol. 23, 5594–5605 (2003).
Tsumura, A. et al. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11, 805–814 (2006).
Meissner, A. Epigenetic modifications in pluripotent and differentiated cells. Nature Biotech. 28, 1079–1088 (2010).
Reik, W., Dean, W. & Walter, J. Epigenetic reprogramming in mammalian development. Science 293, 1089–1093 (2001).
Bhutani, N. et al. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463, 1042–1047 (2010).
Popp, C. et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463, 1101–1105 (2010).
Foshay, K. M. et al. Embryonic stem cells induce pluripotency in somatic cell fusion through biphasic reprogramming. Mol. Cell 46, 159–170 (2012).
He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).
Gu, T. P. et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477, 606–610 (2011).
Gaspar-Maia, A., Alajem, A., Meshorer, E. & Ramalho-Santos, M. Open chromatin in pluripotency and reprogramming. Nature Rev. Mol. Cell Biol. 12, 36–47 (2011).
Ang, Y. S. et al. Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 145, 183–197 (2011).
Jones, A. & Wang, H. Polycomb repressive complex 2 in embryonic stem cells: an overview. Protein Cell 1, 1056–1062 (2010).
Morey, L. et al. Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells. Cell Stem Cell 10, 47–62 (2012).
O'Loghlen, A. et al. MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation. Cell Stem Cell 10, 33–46 (2012). Shows, together with reference 20, that differential incorporation of alternative PRC1 subunits allows PRC1 to target different genes in ES cells and differentiated cells.
Lee, M. G. et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318, 447–450 (2007).
Agger, K. et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449, 731–734 (2007).
Christensen, J. et al. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell 128, 1063–1076 (2007).
Pasini, D. et al. Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-repressive complex 2. Genes Dev. 22, 1345–1355 (2008).
Adamo, A. et al. LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nature Cell Biol. 13, 652–659 (2011).
Whyte, W. A. et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482, 221–225 (2012).
Meshorer, E. et al. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev. Cell 10, 105–116 (2006).
Fussner, E. et al. Constitutive heterochromatin reorganization during somatic cell reprogramming. EMBO J. 30, 1778–1789 (2011).
Gao, Q. et al. Telomeric transgenes are silenced in adult mouse tissues and embryo fibroblasts but are expressed in embryonic stem cells. Stem Cells 25, 3085–3092 (2007).
Ma, D. K., Chiang, C. H., Ponnusamy, K., Ming, G. L. & Song, H. G9a and Jhdm2a regulate embryonic stem cell fusion-induced reprogramming of adult neural stem cells. Stem Cells 26, 2131–2141 (2008).
Shi, Y. et al. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3, 568–574 (2008).
Epsztejn-Litman, S. et al. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nature Struct. Mol. Biol. 15, 1176–1183 (2008).
Lienert, F. et al. Genomic prevalence of heterochromatic H3K9me2 and transcription do not discriminate pluripotent from terminally differentiated cells. PLoS Genet. 7, e1002090 (2011).
Davie, J. R. & Chadee, D. N. Regulation and regulatory parameters of histone modifications. J. Cell Biochem. Suppl. 30–31, 203–213 (1998).
Kidder, B. L., Palmer, S. & Knott, J. G. SWI/SNF-Brg1 regulates self-renewal and occupies core pluripotency-related genes in embryonic stem cells. Stem Cells 27, 317–328 (2009).
Yan, Z. et al. BAF250B-associated SWI/SNF chromatin-remodeling complex is required to maintain undifferentiated mouse embryonic stem cells. Stem Cells 26, 1155–1165 (2008).
Gao, X. et al. ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a. Proc. Natl Acad. Sci. USA 105, 6656–6661 (2008).
Ho, L. et al. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nature Cell Biol. 13, 903–913 (2011).
Fazzio, T. G. & Panning, B. Control of embryonic stem cell identity by nucleosome remodeling enzymes. Curr. Opin. Genet. Dev. 20, 500–504 (2010).
Yildirim, O. et al. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147, 1498–1510 (2011).
Tolhuis, B., Palstra, R. J., Splinter, E., Grosveld, F. & de Laat, W. Looping and interaction between hypersensitive sites in the active β-globin locus. Mol. Cell 10, 1453–1465 (2002).
Palstra, R. J. et al. The β-globin nuclear compartment in development and erythroid differentiation. Nature Genet. 35, 190–194 (2003).
Levasseur, D. N., Wang, J., Dorschner, M. O., Stamatoyannopoulos, J. A. & Orkin, S. H. Oct4 dependence of chromatin structure within the extended Nanog locus in ES cells. Genes Dev. 22, 575–580 (2008).
Donohoe, M. E., Silva, S. S., Pinter, S. F., Xu, N. & Lee, J. T. The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting. Nature 460, 128–132 (2009).
Kim, Y. J., Cecchini, K. R. & Kim, T. H. Conserved, developmentally regulated mechanism couples chromosomal looping and heterochromatin barrier activity at the homeobox gene A locus. Proc. Natl Acad. Sci. USA 108, 7391–7396 (2011). Finds that OCT4 regulates the formation of chromatin loop domains by modulating the binding of cohesin, and that perturbation of higher-order chromatin structure results in dramatic locus-wide gene expression changes.
Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010).
Bertani, S., Sauer, S., Bolotin, E. & Sauer, F. The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. Mol. Cell 43, 1040–1046 (2011).
Wang, K. C. et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120–124 (2011).
Khalil, A. M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl Acad. Sci. USA 106, 11667–11672 (2009).
Tsai, M. C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).
Morey, C., Da Silva, N. R., Perry, P. & Bickmore, W. A. Nuclear reorganisation and chromatin decondensation are conserved, but distinct, mechanisms linked to Hox gene activation. Development 134, 909–919 (2007).
Chambeyron, S., Da Silva, N. R., Lawson, K. A. & Bickmore, W. A. Nuclear re-organisation of the Hoxb complex during mouse embryonic development. Development 132, 2215–2223 (2005).
Chambeyron, S. & Bickmore, W. A. Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. Genes Dev. 18, 1119–1130 (2004).
Bartova, E., Krejci, J., Harnicarova, A. & Kozubek, S. Differentiation of human embryonic stem cells induces condensation of chromosome territories and formation of heterochromatin protein 1 foci. Differentiation 76, 24–32 (2008).
Wiblin, A. E., Cui, W., Clark, A. J. & Bickmore, W. A. Distinctive nuclear organisation of centromeres and regions involved in pluripotency in human embryonic stem cells. J. Cell Sci. 118, 3861–3868 (2005).
Harewood, L. et al. The effect of translocation-induced nuclear reorganization on gene expression. Genome Res. 20, 554–564 (2010).
Morey, C., Kress, C. & Bickmore, W. A. Lack of bystander activation shows that localization exterior to chromosome territories is not sufficient to up-regulate gene expression. Genome Res. 19, 1184–1194 (2009).
Morey, C., Da Silva, N. R., Kmita, M., Duboule, D. & Bickmore, W. A. Ectopic nuclear reorganisation driven by a Hoxb1 transgene transposed into Hoxd. J. Cell Sci. 121, 571–577 (2008).
Simonis, M., Kooren, J. & de Laat, W. An evaluation of 3C-based methods to capture DNA interactions. Nature Methods 4, 895–901 (2007).
Handoko, L. et al. CTCF-mediated functional chromatin interactome in pluripotent cells. Nature Genet. 43, 630–638 (2011). Maps genome-wide CTCF-mediated chromatin interactions in mouse ES cells by using ChIA-PET. Identifies five types of distinct CTCF-associated chromatin domains and a surprising role of CTCF in bridging enhancers and promoters.
de Wit, E. & de Laat, W. A decade of 3C technologies: insights into nuclear organization. Genes Dev. 26, 11–24 (2012).
Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012). Investigates the spatial genome organization of the XIC using 5C in mouse ES cells, neuronal progenitors and MEFs. Reveals several of topologically distinct domains, termed topologically associating domains.
Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).
Dostie, J. et al. Chromosome conformation capture carbon copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res. 16, 1299–1309 (2006).
Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012). Reveals that the genome is organized into large, discrete, self-interacting topological domains by using Hi-C analysis in ES cells and differentiated cells. Topological domains are evolutionarily conserved.
Peric-Hupkes, D. et al. Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol. Cell 38, 603–613 (2010). Shows that expression levels of pluripotency or lineage-specific genes are negatively correlated to the interaction strengths between these gene loci and the nuclear lamina during mouse ES cell differentiation.
Kim, Y. et al. Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells. Science 334, 1706–1710 (2011). Shows that lamin proteins are not required for self-renewal and pluripotency of mouse ES cells.
Meshorer, E. & Misteli, T. Chromatin in pluripotent embryonic stem cells and differentiation. Nature Rev. Mol. Cell Biol. 7, 540–546 (2006).
Tilgner, K., Wojciechowicz, K., Jahoda, C., Hutchison, C. & Markiewicz, E. Dynamic complexes of A-type lamins and emerin influence adipogenic capacity of the cell via nucleocytoplasmic distribution of β-catenin. J. Cell Sci. 122, 401–413 (2009).
Zhang, X. et al. SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice. Neuron 64, 173–187 (2009).
Dauer, W. T. & Worman, H. J. The nuclear envelope as a signaling node in development and disease. Dev. Cell 17, 626–638 (2009).
Asally, M. et al. Nup358, a nucleoporin, functions as a key determinant of the nuclear pore complex structure remodeling during skeletal myogenesis. FEBS J. 278, 610–621 (2011).
Liu, G. H. et al. Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome. Nature 472, 221–225 (2011). Shows that premature ageing-associated nuclear envelope defects and epigenetic abnormalities are reset during reprogramming of HGPS fibroblasts towards iPS cells, and that they reoccur after differentiation towards mesodermal cells.
Verstraeten, V. L. et al. Reorganization of the nuclear lamina and cytoskeleton in adipogenesis. Histochem. Cell Biol. 135, 251–261 (2011).
Constantinescu, D., Gray, H. L., Sammak, P. J., Schatten, G. P. & Csoka, A. B. Lamin A/C expression is a marker of mouse and human embryonic stem cell differentiation. Stem Cells 24, 177–185 (2006).
Zhang, J. et al. A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8, 31–45 (2011).
Liu, G. H. et al. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell 8, 688–694 (2011).
Bhattacharya, D., Talwar, S., Mazumder, A. & Shivashankar, G. V. Spatio-temporal plasticity in chromatin organization in mouse cell differentiation and during Drosophila embryogenesis. Biophys. J. 96, 3832–3839 (2009).
Pajerowski, J. D., Dahl, K. N., Zhong, F. L., Sammak, P. J. & Discher, D. E. Physical plasticity of the nucleus in stem cell differentiation. Proc. Natl Acad. Sci. USA 104, 15619–15624 (2007).
Smith, E. R., Zhang, X. Y., Capo-Chichi, C. D., Chen, X. & Xu, X. X. Increased expression of Syne1/nesprin-1 facilitates nuclear envelope structure changes in embryonic stem cell differentiation. Dev. Dyn. 240, 2245–2255 (2011).
Sullivan, T. et al. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J. Cell Biol. 147, 913–920 (1999).
Li, W. et al. Decreased bone formation and osteopenia in lamin a/c-deficient mice. PLoS ONE 6, e19313 (2011).
Marchetto, M. C. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).
Samaco, R. C. & Neul, J. L. Complexities of Rett syndrome and MeCP2. J. Neurosci. 31, 7951–7959 (2011).
Muotri, A. R. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010).
Ho, J. C. et al. Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C. Aging (Albany NY) 3, 380–390 (2011).
Soldner, F. et al. Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146, 318–331 (2011).
Hockemeyer, D. & Jaenisch, R. Gene targeting in human pluripotent cells. Cold Spring Harb. Symp. Quant. Biol. 75, 201–209 (2010).
Liu, G. H., Sancho-Martinez, I. & Izpisua Belmonte, J. C. Cut and paste: restoring cellular function by gene correction. Cell Res. 22, 283–284 (2012).
Sancho-Martinez, I., Li, M. & Izpisua Belmonte, J. C. Disease correction the iPSC way: advances in iPSC-based therapy. Clin. Pharmacol. Ther. 89, 746–749 (2011).
Hockemeyer, D. et al. Genetic engineering of human pluripotent cells using TALE nucleases. Nature Biotech. 29, 731–734 (2011).
Li, M. et al. Efficient correction of hemoglobinopathy-causing mutations by homologous recombination in integration-free patient iPSCs. Cell Res. 21, 1740–1744 (2011). Describes, together with references 80 and 94, two novel gene-editing technologies, which can be used to efficiently engineer human pluripotent stem cells to manipulate and study epigenetic pathways.
Guenther, M. G. et al. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7, 249–257 (2010).
Stock, J. K. et al. Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nature Cell Biol. 9, 1428–1435 (2007).
Eskeland, R. et al. Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination. Mol. Cell 38, 452–464 (2010).
Leeb, M. et al. Polycomb complexes act redundantly to repress genomic repeats and genes. Genes Dev. 24, 265–276 (2010).
Chamberlain, S. J., Yee, D. & Magnuson, T. Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells 26, 1496–1505 (2008).
Pasini, D. et al. Regulation of stem cell differentiation by histone methyltransferases and demethylases. Cold Spring Harb. Symp. Quant. Biol. 73, 253–263 (2008).
Zhao, X. D. et al. Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell 1, 286–298 (2007).
Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).
Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).
Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).
Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science 295, 1306–1311 (2002).
Schneider, R. & Grosschedl, R. Dynamics and interplay of nuclear architecture, genome organization, and gene expression. Genes Dev. 21, 3027–3043 (2007).
Dechat, T. et al. Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev. 22, 832–853 (2008).
Masny, P. S. et al. Localization of 4q35.2 to the nuclear periphery: is FSHD a nuclear envelope disease? Hum. Mol. Genet. 13, 1857–1871 (2004).
Nikolova, V. et al. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J. Clin. Invest. 113, 357–369 (2004).
Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).
Acknowledgements
The authors apologize to those colleagues whose work could not be cited due to space constraint. We would like to thank M. J. Barrero, N.Y. Kim, M. Schwarz, P. Schwarz and I. Dubova for critical reading of the manuscript. We thank N.Y. Kim for rendering the schematic model of topological domains. G.H.L. was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences. This study was supported by grants from the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi, Ellison Medical Foundation, The Leona M. and Harry B. Helmsley Charitable Trust, the Glenn Foundation for Medical Research, Ministerio de Economía y Competitividad (MINECO) and Fundacion Cellex (J.C.I.B.).
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Glossary
- Induced pluripotent stem cells
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(iPS cells). Somatic cells that have been reprogrammed to a pluripotent state, which is highly similar to that of embryonic stem cells. iPS cells were first generated by the Yamanaka group in 2006 from mouse somatic cells by enforced expression of OCT4, SOX2, KLF4 (Krüppel-like factor 4) and c-MYC. iPS cells have been successfully derived from somatic cells of different species through overexpression of various combinations of factors.
- Somatic reprogramming
-
Specifically referred to as reprogramming of somatic cells towards pluripotency, which entails the erasure of epigenetic marks of somatic cell origin and re-establishment of pluripotency-specific transcriptional and epigenetic programmes. The three major approaches for somatic reprogramming are somatic cell nuclear transfer, cell fusion-based reprogramming and transcription factor-based reprogramming.
- Inner cell mass
-
(ICM). Refers to a population of cells inside the early embryo (the blastocyst), which ultimately give rise to all fetal tissues. The ICM is located at the embryonic pole of the blastocyst and is surrounded by a monolayer of trophoblast cells. Mouse embryonic stem cells were initially isolated from ICM.
- Blastomeres
-
Cells formed by cleavage (which is the initial rapid cell divisions after fertilization) during early embryonic development.
- Primordial germ cells
-
(PGCs). The precursors of sperms and eggs. During development, PGCs are specified far from their somatic niche and have to actively migrate to the gonadal ridge to become mature germ cells.
- Activation-induced cytidine deaminase
-
(AID). A factor required for generating antibody diversity by introducing mutations into the immunoglobulin loci in B cells. AID enzymatically converts cytidines into uracils, thus creating mismatches that initiate downstream repair pathways, which produce diversified immunoglobulin sequences. AID can also convert 5mC into thymidine through deamination.
- Heterokaryon-based reprogramming
-
A reprogramming strategy in which somatic cells are reprogrammed by fusion with pluripotent stem cells to create hybrid cells (also known as heterokaryons). Heterokaryon-based reprogramming is rapid, efficient and independent of cell division.
- LIF–STAT3 signalling
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(leukaemia inhibitory factor – signal transducer and activator of transcription 3 signalling). In mouse embryonic stem cells, the binding of LIF to its receptor leads to the activation of the transcription factor STAT3, which is important for the maintenance of self-renewal. The LIF–STAT3 pathway activates many downstream targets, including the pluripotency factors c-MYC, SALL4 and KLF4 (Kürppel-like factor 4), to form a pluripotency transcriptional network.
- Trophectoderm
-
The cell layer from which the trophoblast differentiates. Trophoblasts are the peripheral cells of the blastocyst that develop into a large part of the placenta and the membranes that nourish and protect the developing embryo.
- Insulator protein
-
Regulatory protein that binds to insulator elements in the DNA. DNA-bound insulators can block the communication between enhancers and gene promoters when situated between them. They can act as a barrier to the spread of heterochromatin.
- Cohesin
-
A multiprotein complex that mediates sister chromatid cohesion during cell division. Cohesin is also involved in other processes including DNA double-strand break repair and transcription. Recently, cohesin has been implicated in organizing higher-order chromatin structure.
- Centromeres
-
The sites of sister chromatid cohesion on the chromosome after DNA replication, and the sites of chromosome binding to the mitotic spindle. Eukaryotic centromeres mainly consist of repetitive DNA and are in a heterochromatin state.
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Li, M., Liu, GH. & Belmonte, J. Navigating the epigenetic landscape of pluripotent stem cells. Nat Rev Mol Cell Biol 13, 524–535 (2012). https://doi.org/10.1038/nrm3393
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DOI: https://doi.org/10.1038/nrm3393
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