Pouca importância é creditada às marcas epigenéticas globais durante o desenvolvimento embrionário inicial, e ainda hoje poucos estudos abordam modificações de histona neste tópico. No presente trabalho, demonstramos que modificações globais de histonas estão relacionadas a processos importantes na embriogênese, que variam de forma específica em embriões de classes distintas, incluindo o sexo e qualidade dos mesmos. Ainda, mostramos que modificações de histonas participam da especificação de linhagens, e podem direcionar a diferenciação celular em blastocistos.
A detecção de embriões apresentando níveis variáveis de modificações permissivas e repressivas de histonas pode ser um indício de que as observações feitas pelo grupo da Dra. Magdalena Zernicka-Goetz em camundongos, a respeito dos padrões de clivagens e níveis de modificações de histonas, possivelmente ocorrem em embriões bovinos. Neste sentido, estudos adicionais envolvendo filmes time-lapse para acompanhamento da dinâmica de clivagens no desenvolvimento embrionário bovino seria esclarecedora. Ainda, o monitoramento destas marcas em diferentes sistemas de cultivo e sua comparação com embriões produzidos in vivo representa uma estratégia para monitorar condições estressantes do cultivo in vitro.
A inibição de HDAC pode consistir em uma ferramenta eficaz para incrementar o desenvolvimento embrionário de fêmeas. Mostramos evidências de que os blastocistos fêmeas são mais sensíveis do que os machos aos níveis aumentados de acetilação, e estes incrementos se traduzem na redução da expressão de XIST, sugerindo retardamento no processo de inativação do cromossomo X. Estudos adicionais envolvendo o desenvolvimento pós-implantacional destes embriões seriam úteis no sentido de clarificar se estes efeitos observados após a suplementação de TSA representariam vantagens para o desenvolvimento embrionário de fêmeas. Caso a inativação precoce do cromossomo X seja um efeito indesejável da PIV, a
suplementação com TSA representará uma estratégia para incremento nas taxas de prenhez.
Observamos ainda que PADI4 atua na especificação de linhagens, e sua ativação estimula a formação de células pluripotentes, enquanto sua inibição favorece a diferenciação trofectodérmica. A implicação mais evidente deste resultado seria a possibilidade de produção de embriões mais adequados à derivação de células tronco embrionárias, e utilizar ativadores de PADI4 para induzir e recombinar núcleos celulares à pluripotência. No entanto, o composto GSK106, caracterizado como ativador de PADI4 em células tronco embrionárias e em embriões murinos, não se encontra disponível por estar em fase de teste pelo laboratório do Prof. Tony Kouzarides.
Descrevemos também que a suplementação com o inibidor de PADI4 Cl-amidina resulta em blastocistos com percentual inferior de células pluripotentes. No entanto, estes embriões apresentam maior número de células totais, pelo incremento das células do trofectoderma, mas em contrapartida não apresentam alterações numéricas em células da massa celular interna. Portanto, a Cl-amidina pode ser eficaz na tentativa de produzir embriões com maior número de células do trofectoderma, que podem apresentar maior potencial para implantação. Neste sentido, estudos aplicando a Cl- amidina no cultivo embrionário de blastocistos bovinos podem ser interessantes visando o aumento nas taxas de prenhez alcançadas.
REFERÊNCIAS
ADENOT, P. G. et al. Differential h4 acetylation of paternal and maternal chromatin precedes DNA replication and differential transcriptional activity in pronuclei of 1-cell mouse embryos. Development, v. 124, n. 22, p. 4615-25, 1997.
AHMED, K. et al. Global chromatin architecture reflects pluripotency and lineage commitment in the early mouse embryo. PLoS One, v. 5, n. 5, p. e10531, 2010.
ANTUNES, G. et al. Influence of apoptosis in bovine embryo's development. Reprod Domest Anim, v. 45, n. 1, p. 26-32, 2010.
AOKI, F.; WORRAD, D. M.; SCHULTZ, R. M. Regulation of transcriptional activity during the first and second cell cycles in the preimplantation mouse embryo. Dev Biol, v. 181, n. 2, p. 296-307, 1997.
ASAGA, H. et al. Immunocytochemical localization of peptidylarginine deiminase in human eosinophils and neutrophils. J Leukoc Biol, v. 70, n. 1, p. 46-51, 2001.
AUGUI, S.; NORA, E. P.; HEARD, E. Regulation of x-chromosome inactivation by the x- inactivation centre. Nat Rev Genet, v. 12, n. 6, p. 429-42, 2011.
AVERY, B. et al. Morphological development and sex of bovine invitro-fertilized embryos. Mol Reprod Dev, v. 32, n. 3, p. 265-270, 1992.
BADR, H. et al. Gene expression in the in vitro-produced preimplantation bovine embryos. Zygote, v. 15, n. 4, p. 355-67, 2007.
BANNISTER, A. J.; KOUZARIDES, T. Reversing histone methylation. Nature, v. 436, n. 7054, p. 1103-6, 2005.
BANNISTER, A. J.; KOUZARIDES, T. Regulation of chromatin by histone modifications. Cell Res, v. 21, n. 3, p. 381-95, 2011.
BASRUR, P. K. et al. Expression pattern of x-linked genes in sex chromosome aneuploid bovine cells. Chromosome Res, v. 12, n. 3, p. 263-73, 2004.
BASTOS, G. M.; GONÇALVES, P. B.; BORDIGNON, V. Immunolocalization of the high- mobility group n2 protein and acetylated histone h3k14 in early developing parthenogenetic bovine embryos derived from oocytes of high and low developmental competence. Mol Reprod Dev, v. 75, n. 2, p. 282-90, 2008.
BENSAUDE, O. et al. Heat shock proteins, first major products of zygotic gene activity in mouse embryo. Nature, v. 305, n. 5932, p. 331-3, 1983.
BERMEJO-ALVAREZ, P. et al. Transcriptional sexual dimorphism in elongating bovine embryos: Implications for xci and sex determination genes. Reproduction, v. 141, n. 6, p. 801-8, 2011.
BERMEJO-ALVAREZ, P. et al. Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts. Proc Natl Acad Sci U S A, v. 107, n. 8, p. 3394-9, 2010.
BERTOLINI, M. et al. Morphology and morphometry of in vivo- and in vitro-produced bovine concepti from early pregnancy to term and association with high birth weights. Theriogenology, v. 58, n. 5, p. 973-94, 2002.
BETTS, D. H.; KING, W. A. Genetic regulation of embryo death and senescence. Theriogenology, v. 55, n. 1, p. 171-91, 2001.
BISCHOFF, M.; PARFITT, D. E.; ZERNICKA-GOETZ, M. Formation of the embryonic- abembryonic axis of the mouse blastocyst: Relationships between orientation of early cleavage divisions and pattern of symmetric/asymmetric divisions. Development, v. 135, n. 5, p. 953-62, 2008.
BRACKETT, B. G. et al. Normal development following in vitro fertilization in the cow. Biol Reprod, v. 27, n. 1, p. 147-58, 1982.
BRAUDE, P.; BOLTON, V.; MOORE, S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature, v. 332, n. 6163, p. 459-61, 1988.
BRINSKO, S. P. et al. Initiation of transcription and nucleologenesis in equine embryos. Mol Reprod Dev, v. 42, n. 3, p. 298-302, 1995.
BRUNET-SIMON, A. et al. Onset of zygotic transcription and maternal transcript legacy in the rabbit embryo. Mol Reprod Dev, v. 58, n. 2, p. 127-36, 2001.
COCKBURN, K.; ROSSANT, J. Making the blastocyst: Lessons from the mouse. J Clin Invest, v. 120, n. 4, p. 995-1003, 2010.
CROSBY, I. M.; GANDOLFI, F.; MOOR, R. M. Control of protein synthesis during early cleavage of sheep embryos. J Reprod Fertil, v. 82, n. 2, p. 769-75, 1988.
CRUZ, Y. P.; PEDERSEN, R. A. Cell fate in the polar trophectoderm of mouse blastocysts as studied by microinjection of cell lineage tracers. Dev Biol, v. 112, n. 1, p. 73-83, 1985.
CUTHBERT, G. L. et al. Histone deimination antagonizes arginine methylation. Cell, v. 118, n. 5, p. 545-53, 2004.
DAHL, J. A. et al. Histone h3 lysine 27 methylation asymmetry on developmentally- regulated promoters distinguish the first two lineages in mouse preimplantation embryos. PLoS One, v. 5, n. 2, p. e9150, 2010.
DAI, B.; RASMUSSEN, T. P. Global epiproteomic signatures distinguish embryonic stem cells from differentiated cells. Stem Cells, v. 25, n. 10, p. 2567-74, 2007.
DALCQ, A. Introduction to general embryology. 1. London: Oxford University Press, 1957. 177
DAVIS, W.; SCHULTZ, R. M. Role of the first round of DNA replication in reprogramming gene expression in the preimplantation mouse embryo. Mol Reprod Dev, v. 47, n. 4, p. 430-4, 1997.
DE LA FUENTE, R. et al. X inactive-specific transcript (xist) expression and x chromosome inactivation in the preattachment bovine embryo. Biol Reprod, v. 60, n. 3, p. 769-75, 1999.
DE SOUSA, P. A.; WATSON, A. J.; SCHULTZ, R. M. Transient expression of a translation initiation factor is conservatively associated with embryonic gene activation in murine and bovine embryos. Biol Reprod, v. 59, n. 4, p. 969-77, 1998.
DEAN, W.; SANTOS, F.; REIK, W. Epigenetic reprogramming in early mammalian development and following somatic nuclear transfer. Semin Cell Dev Biol, v. 14, n. 1, p. 93-100, 2003.
DEAN, W. et al. Conservation of methylation reprogramming in mammalian development: Aberrant reprogramming in cloned embryos. Proc Natl Acad Sci U S A, v. 98, n. 24, p. 13734-8, 2001.
DIETRICH, J. E.; HIIRAGI, T. Stochastic patterning in the mouse pre-implantation embryo. Development, v. 134, n. 23, p. 4219-31, 2007.
DING, X. et al. Increased pre-implantation development of cloned bovine embryos treated with 5-aza-2'-deoxycytidine and trichostatin a. Theriogenology, v. 70, n. 4, p. 622-30, 2008.
DYCE, J. et al. Do trophectoderm and inner cell mass cells in the mouse blastocyst maintain discrete lineages? Development, v. 100, n. 4, p. 685-98, 1987.
EDWARDS, J. et al. Responsiveness of early embryos to environmental insults: Potential protective roles of hsp70 and glutathione. Theriogenology, v. 55, n. 1, p. 209- 223, 2001.
ENRIGHT, B. P. et al. Epigenetic characteristics of bovine donor cells for nuclear transfer: Levels of histone acetylation. Biol Reprod, v. 69, n. 5, p. 1525-30, 2003.
ERHARDT, S. et al. Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development. Development, v. 130, n. 18, p. 4235-48, 2003.
FLEMING, T. P. et al. Trophectodermal processes regulate the expression of totipotency within the inner cell mass of the mouse expanding blastocyst. J Embryol Exp Morphol, v. 84, p. 63-90, 1984.
FOULADI-NASHTA, A. A. et al. Differential staining combined with tunel labelling to detect apoptosis in preimplantation bovine embryos. Reprod Biomed Online, v. 10, n. 4, p. 497-502, 2005.
GARDNER, R. L. The early blastocyst is bilaterally symmetrical and its axis of symmetry is aligned with the animal-vegetal axis of the zygote in the mouse. Development, v. 124, n. 2, p. 289-301, 1997.
GARDNER, R. L. Experimental analysis of second cleavage in the mouse. Hum Reprod, v. 17, n. 12, p. 3178-89, 2002.
GOLOB, J. L. et al. Chromatin remodeling during mouse and human embryonic stem cell differentiation. Dev Dyn, v. 237, n. 5, p. 1389-98, 2008.
GRAY, D. et al. First cleavage of the mouse embryo responds to change in egg shape at fertilization. Curr Biol, v. 14, n. 5, p. 397-405, 2004.
GURDON, J. B. The generation of diversity and pattern in animal development. Cell, v. 68, n. 2, p. 185-99, 1992.
HADJANTONAKIS, A. K.; PAPAIOANNOU, V. E. Dynamic in vivo imaging and cell tracking using a histone fluorescent protein fusion in mice. BMC Biotechnol, v. 4, p. 33, 2004.
HAMATANI, T. et al. Global gene expression profiling of preimplantation embryos. Hum Cell, v. 19, n. 3, p. 98-117, 2006.
HEARD, E. Delving into the diversity of facultative heterochromatin: The epigenetics of the inactive x chromosome. Curr Opin Genet Dev, v. 15, n. 5, p. 482-9, 2005.
IAGER, A. E. et al. Trichostatin a improves histone acetylation in bovine somatic cell nuclear transfer early embryos. Cloning Stem Cells, v. 10, n. 3, p. 371-9, 2008.
IKEDA, S. et al. Enhancement of histone acetylation by trichostatin a during in vitro fertilization of bovine oocytes affects cell number of the inner cell mass of the resulting blastocysts. Zygote, v. 17, n. 3, p. 209-15, 2009.
JEDRUSIK, A. et al. Role of cdx2 and cell polarity in cell allocation and specification of trophectoderm and inner cell mass in the mouse embryo. Genes Dev, v. 22, n. 19, p. 2692-706, 2008.
JOHNSON, M. H. From mouse egg to mouse embryo: Polarities, axes, and tissues. Annu Rev Cell Dev Biol, v. 25, p. 483-512, 2009.
JOHNSON, M. H.; ZIOMEK, C. A. The foundation of two distinct cell lineages within the mouse morula. Cell, v. 24, n. 1, p. 71-80, 1981.
JOHNSTONE, R. W. Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer. Nat Rev Drug Discov, v. 1, n. 4, p. 287-99, 2002.
JOUSAN, F. D. et al. Relationship between group ii caspase activity of bovine preimplantation embryos and capacity for hatching. J Reprod Dev, v. 54, n. 3, p. 217- 20, 2008.
KANG, Y. K. et al. Limited demethylation leaves mosaic-type methylation states in cloned bovine pre-implantation embryos. EMBO J, v. 21, n. 5, p. 1092-100, 2002.
KIM, J. M. et al. Changes in histone acetylation during mouse oocyte meiosis. J Cell Biol, v. 162, n. 1, p. 37-46, 2003.
KORNBERG, R. D. Chromatin structure: A repeating unit of histones and DNA. Science, v. 184, n. 4139, p. 868-71, 1974.
KORNBERG, R. D.; THOMAS, J. O. Chromatin structure; oligomers of the histones. Science, v. 184, n. 4139, p. 865-8, 1974.
KOUZARIDES, T. Chromatin modifications and their function. Cell, v. 128, n. 4, p. 693- 705, 2007.
KOYAMA, Y. et al. Histone deacetylase inhibitors suppress il-2-mediated gene expression prior to induction of apoptosis. Blood, v. 96, n. 4, p. 1490-5, 2000.
KUROTAKI, Y. et al. Blastocyst axis is specified independently of early cell lineage but aligns with the zp shape. Science, v. 316, n. 5825, p. 719-23, 2007.
LEVY, J. B. et al. The timing of compaction: Control of a major developmental transition in mouse early embryogenesis. J Embryol Exp Morphol, v. 95, p. 213-37, 1986.
LI, E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet, v. 3, n. 9, p. 662-73, 2002.
LONERGAN, P. Growth of preimplantation bovine embryos. Acta Vet Scand, v. 35, n. 4, p. 307-20, 1994.
LONERGAN, P. et al. Oocyte and embryo quality: Effect of origin, culture conditions and gene expression patterns. Reprod Domest Anim, v. 38, n. 4, p. 259-67, 2003. LOPES, A. S. et al. Respiration rates correlate with mrna expression of g6pd and glut1 genes in individual bovine in vitro-produced blastocysts. Theriogenology, v. 68, n. 2, p. 223-36, 2007.
MA, P.; SCHULTZ, R. M. Histone deacetylase 1 (hdac1) regulates histone acetylation, development, and gene expression in preimplantation mouse embryos. Dev Biol, v. 319, n. 1, p. 110-20, 2008.
MAALOUF, W. E.; ALBERIO, R.; CAMPBELL, K. H. Differential acetylation of histone h4 lysine during development of in vitro fertilized, cloned and parthenogenetically activated bovine embryos. Epigenetics, v. 3, n. 4, p. 199-209, 2008.
MARTIN, C.; ZHANG, Y. The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol, v. 6, n. 11, p. 838-49, 2005.
MCGRAW, S. et al. Quantification of histone acetyltransferase and histone deacetylase transcripts during early bovine embryo development. Biol Reprod, v. 68, n. 2, p. 383-9, 2003.
MCLAREN, A. Mammalian chimaeras. Cambridge: Cambridge University Press, 1976. MEIRELLES, F. V. et al. Genome activation and developmental block in bovine embryos. Anim Reprod Sci, v. 82-83, p. 13-20, 2004.
MEMILI, E.; FIRST, N. L. Zygotic and embryonic gene expression in cow: A review of timing and mechanisms of early gene expression as compared with other species. Zygote, v. 8, n. 1, p. 87-96, 2000.
MERIGHE, G. et al. Gene silencing during development of in vitro-produced female bovine embryos. Genetics and Molecular Research, v. 8, n. 3, p. 1116-1127, 2009. MINTZ, B. Genetic mosaicism in adult mice of quadriparental lineage. Science, v. 148, n. 3674, p. 1232-3, 1965.
MOORE, G. P. The rna polymerase activity of the preimplantation mouse embryo. J Embryol Exp Morphol, v. 34, n. 2, p. 291-8, 1975.
MOTOSUGI, N. et al. Polarity of the mouse embryo is established at blastocyst and is not prepatterned. Genes Dev, v. 19, n. 9, p. 1081-92, 2005.
NAGY, A. et al. Manipulating the mouse embryo. New York: Cold Spring Harbor Laboratory Press, 2003.
NERVI, C. et al. Inhibition of histone deacetylase activity by trichostatin a modulates gene expression during mouse embryogenesis without apparent toxicity. Cancer Res, v. 61, n. 4, p. 1247-9, 2001.
NINO-SOTO, M. I.; BASRUR, P. K.; KING, W. A. Impact of in vitro production techniques on the expression of x-linked genes in bovine (bos taurus) oocytes and pre- attachment embryos. Mol Reprod Dev, v. 74, n. 2, p. 144-53, 2007.
NOTHIAS, J. Y.; MIRANDA, M.; DEPAMPHILIS, M. L. Uncoupling of transcription and translation during zygotic gene activation in the mouse. EMBO J, v. 15, n. 20, p. 5715- 25, 1996.
O'NEILL, L. P. et al. A developmental switch in h4 acetylation upstream of xist plays a role in x chromosome inactivation. EMBO J, v. 18, n. 10, p. 2897-907, 1999.
OTA, M.; SASAKI, H. Mammalian tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of hippo signaling. Development, v. 135, n. 24, p. 4059-69, 2008.
PARFITT, D. E.; ZERNICKA-GOETZ, M. Epigenetic modification affecting expression of cell polarity and cell fate genes to regulate lineage specification in the early mouse embryo. Mol Biol Cell, v. 21, n. 15, p. 2649-60, 2010.
PATTERTON, D.; WOLFFE, A. P. Developmental roles for chromatin and chromosomal structure. Dev Biol, v. 173, n. 1, p. 2-13, 1996.
PAULA-LOPES, F. F.; HANSEN, P. J. Apoptosis is an adaptive response in bovine preimplantation embryos that facilitates survival after heat shock. Biochem Biophys Res Commun, v. 295, n. 1, p. 37-42, 2002.
PAULA-LOPES, F. F.; HANSEN, P. J. Heat shock-induced apoptosis in preimplantation bovine embryos is a developmentally regulated phenomenon. Biol Reprod, v. 66, n. 4, p. 1169-77, 2002.
PEDERSEN, R. A.; WU, K.; BAŁAKIER, H. Origin of the inner cell mass in mouse embryos: Cell lineage analysis by microinjection. Dev Biol, v. 117, n. 2, p. 581-95, 1986. PIOTROWSKA-NITSCHE, K. et al. Four-cell stage mouse blastomeres have different developmental properties. Development, v. 132, n. 3, p. 479-90, 2005.
PIOTROWSKA-NITSCHE, K.; ZERNICKA-GOETZ, M. Spatial arrangement of individual 4-cell stage blastomeres and the order in which they are generated correlate with blastocyst pattern in the mouse embryo. Mech Dev, v. 122, n. 4, p. 487-500, 2005. PLACHTA, N. et al. Oct4 kinetics predict cell lineage patterning in the early mammalian embryo. Nat Cell Biol, v. 13, n. 2, p. 117-23, 2011.
PLUSA, B. et al. Downregulation of par3 and apkc function directs cells towards the icm in the preimplantation mouse embryo. J Cell Sci, v. 118, n. Pt 3, p. 505-15, 2005.
RAMBHATLA, L.; LATHAM, K. E. Strain-specific progression of alpha-amanitin-treated mouse embryos beyond the two-cell stage. Mol Reprod Dev, v. 41, n. 1, p. 16-9, 1995. REIK, W.; SANTOS, F.; DEAN, W. Mammalian epigenomics: Reprogramming the genome for development and therapy. Theriogenology, v. 59, n. 1, p. 21-32, 2003. RIZOS, D. et al. Analysis of differential messenger rna expression between bovine blastocysts produced in different culture systems: Implications for blastocyst quality. Biol Reprod, v. 66, n. 3, p. 589-95, 2002.
ROSSANT, J. Postimplantation development of blastomeres isolated from 4- and 8-cell mouse eggs. J Embryol Exp Morphol, v. 36, n. 2, p. 283-90, 1976.
ROSSANT, J.; VIJH, K. M. Ability of outside cells from preimplantation mouse embryos to form inner cell mass derivatives. Dev Biol, v. 76, n. 2, p. 475-82, 1980.
RUGG-GUNN, P. J. et al. Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo. Proc Natl Acad Sci U S A, v. 107, n. 24, p. 10783-90, 2010.
SANTOS, F. et al. Epigenetic marking correlates with developmental potential in cloned bovine preimplantation embryos. Curr Biol, v. 13, n. 13, p. 1116-21, 2003.
SANZ, L. A.; KOTA, S. K.; FEIL, R. Genome-wide DNA demethylation in mammals. Genome Biol, v. 11, n. 3, p. 110, 2010.
SARAIVA, N. Z. et al. Chemically-assisted enucleation results in higher G6PD expression in early bovine female embryos obtained by somatic cell nuclear transfer. Cellular Reprogramming, no prelo.
SARMENTO, O. F. et al. Dynamic alterations of specific histone modifications during early murine development. J Cell Sci, v. 117, n. Pt 19, p. 4449-59, 2004.
SCHNABEL, R. et al. Assessing normal embryogenesis in caenorhabditis elegans using a 4d microscope: Variability of development and regional specification. Dev Biol, v. 184, n. 2, p. 234-65, 1997.
SCHRAMM, R. D.; BAVISTER, B. D. Onset of nucleolar and extranucleolar transcription and expression of fibrillarin in macaque embryos developing in vitro. Biol Reprod, v. 60, n. 3, p. 721-8, 1999.
SCHÜBELER, D. et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev, v. 18, n. 11, p. 1263-71, 2004.
SCHULTZ, R. M. The molecular foundations of the maternal to zygotic transition in the preimplantation embryo. Hum Reprod Update, v. 8, n. 4, p. 323-31, 2002.
SLACK, J. L.; CAUSEY, C. P.; THOMPSON, P. R. Protein arginine deiminase 4: A target for an epigenetic cancer therapy. Cell Mol Life Sci, v. 68, n. 4, p. 709-20, 2011. SPINACI, M.; SEREN, E.; MATTIOLI, M. Maternal chromatin remodeling during maturation and after fertilization in mouse oocytes. Mol Reprod Dev, v. 69, n. 2, p. 215- 21, 2004.
SUTHERLAND, A. E.; SPEED, T. P.; CALARCO, P. G. Inner cell allocation in the mouse morula: The role of oriented division during fourth cleavage. Dev Biol, v. 137, n. 1, p. 13-25, 1990.
SUWIŃSKA, A. et al. Blastomeres of the mouse embryo lose totipotency after the fifth cleavage division: Expression of cdx2 and oct4 and developmental potential of inner and outer blastomeres of 16- and 32-cell embryos. Dev Biol, v. 322, n. 1, p. 133-44, 2008. TARKOWSKI, A. K. Experiments on the development of isolated blastomers of mouse eggs. Nature, v. 184, p. 1286-7, 1959.
TARKOWSKI, A. K. Mouse chimaeras developed from fused eggs. Nature, v. 190, p. 857-60, 1961.
TARKOWSKI, A. K.; OZDZENSKI, W.; CZOŁOWSKA, R. Mouse singletons and twins developed from isolated diploid blastomeres supported with tetraploid blastomeres. Int J Dev Biol, v. 45, n. 3, p. 591-6, 2001.
TARKOWSKI, A. K.; WRÓBLEWSKA, J. Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage. J Embryol Exp Morphol, v. 18, n. 1, p. 155-80, 1967.
TESARÍK, J. et al. Early morphological signs of embryonic genome expression in human preimplantation development as revealed by quantitative electron microscopy. Dev Biol, v. 128, n. 1, p. 15-20, 1988.
THIEFFRY, D. Rationalizing early embryogenesis in the 1930s: Albert dalcq on gradients and fields. J Hist Biol, v. 34, n. 1, p. 149-81, 2001.
THOMPSON, P. R.; FAST, W. Histone citrullination by protein arginine deiminase: Is arginine methylation a green light or a roadblock? ACS Chem Biol, v. 1, n. 7, p. 433-41, 2006.
TORRES-PADILLA, M. E. et al. Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature, v. 445, n. 7124, p. 214-8, 2007.
TSUNODA, Y.; MCLAREN, A. Effect of various procedures on the viability of mouse embryos containing half the normal number of blastomeres. J Reprod Fertil, v. 69, n. 1, p. 315-22, 1983.
TURNER, B. M. Defining an epigenetic code. Nat Cell Biol, v. 9, n. 1, p. 2-6, 2007. VASSENA, R. et al. Waves of early transcriptional activation and pluripotency program initiation during human preimplantation development. Development, v. 138, n. 17, p. 3699-709, 2011.
WANG, H.; DEY, S. K. Roadmap to embryo implantation: Clues from mouse models. Nat Rev Genet, v. 7, n. 3, p. 185-99, 2006.
WANG, Y. et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol, v. 184, n. 2, p. 205-13, 2009.
WANG, Y. et al. Human pad4 regulates histone arginine methylation levels via demethylimination. Science, v. 306, n. 5694, p. 279-83, 2004.
WEE, G. et al. Epigenetic alteration of the donor cells does not recapitulate the reprogramming of DNA methylation in cloned embryos. Reproduction, v. 134, n. 6, p. 781-7, 2007.
WEINHOLD, B. Epigenetics: The science of change. Environ Health Perspect, v. 114, n. 3, p. A160-7, 2006.
WOLFFE, A. P.; GUSCHIN, D. Review: Chromatin structural features and targets that regulate transcription. J Struct Biol, v. 129, n. 2-3, p. 102-22, 2000.
WRENZYCKI, C. et al. Expression of the gap junction gene connexin43 (cx43) in preimplantation bovine embryos derived in vitro or in vivo. J Reprod Fertil, v. 108, n. 1, p. 17-24, 1996.
WRENZYCKI, C. et al. Gene expression patterns in in vitro-produced and somatic nuclear transfer-derived preimplantation bovine embryos: Relationship to the large offspring syndrome? Anim Reprod Sci, v. 82-83, p. 593-603, 2004.
WRENZYCKI, C. et al. In vitro production and nuclear transfer affect dosage compensation of the x-linked gene transcripts g6pd, pgk, and xist in preimplantation bovine embryos. Biol Reprod, v. 66, n. 1, p. 127-34, 2002.
WU, Q. et al. Carm1 is required in embryonic stem cells to maintain pluripotency and resist differentiation. Stem Cells, v. 27, n. 11, p. 2637-45, 2009.
WYSOCKA, J.; ALLIS, C. D.; COONROD, S. Histone arginine methylation and its dynamic regulation. Front Biosci, v. 11, p. 344-55, 2006.
XU, K. et al. Sex-related differences in developmental rates of bovine embryos produced and cultured invitro. Molecular Reproduction and Development, v. 31, n. 4, p. 249-252, 1992.
YAKOVLEV, A. et al. Epigenetic regulation of caspase-3 gene expression in rat brain development. Gene, v. 450, n. 1-2, p. 103-8, 2010.
YANG, X. et al. Nuclear reprogramming of cloned embryos and its implications for therapeutic cloning. Nat Genet, v. 39, n. 3, p. 295-302, 2007.
ZERNICKA-GOETZ, M. Cleavage pattern and emerging asymmetry of the mouse embryo. Nat Rev Mol Cell Biol, v. 6, n. 12, p. 919-28, 2005.
ZERNICKA-GOETZ, M.; HUANG, S. Stochasticity versus determinism in development: A false dichotomy? Nat Rev Genet, v. 11, n. 11, p. 743-4, 2010.
ZERNICKA-GOETZ, M.; MORRIS, S. A.; BRUCE, A. W. Making a firm decision: Multifaceted regulation of cell fate in the early mouse embryo. Nat Rev Genet, v. 10, n. 7, p. 467-77, 2009.
ZUPKOVITZ, G. et al. Negative and positive regulation of gene expression by mouse histone deacetylase 1. Mol Cell Biol, v. 26, n. 21, p. 7913-28, 2006.