Dynamic alterations in the paternal epigenetic landscape following fertilization

Timothy G Jenkins, Douglas T Carrell, Timothy G Jenkins, Douglas T Carrell

Abstract

Embryonic development is a complex and dynamic process with frequent changes in gene expression, ultimately leading to cellular differentiation and commitment of various cell lines. These changes are likely preceded by changes to signaling cascades and/or alterations to the epigenetic program in specific cells. The process of epigenetic remodeling begins early in development. In fact, soon after the union of sperm and egg massive epigenetic changes occur across the paternal and maternal epigenetic landscape. The epigenome of these cells includes modifications to the DNA itself, in the form of DNA methylation, as well as nuclear protein content and modification, such as modifications to histones. Sperm chromatin is predominantly packaged by protamines, but following fertilization the sperm pronucleus undergoes remodeling in which maternally derived histones replace protamines, resulting in the relaxation of chromatin and ultimately decondensation of the paternal pronucleus. In addition, active DNA demethylation occurs across the paternal genome prior to the first cell division, effectively erasing many spermatogenesis derived methylation marks. This complex interplay begins the dynamic process by which two haploid cells unite to form a diploid organism. The biology of these events is central to the understanding of sexual reproduction, yet our knowledge regarding the mechanisms involved is extremely limited. This review will explore what is known regarding the post-fertilization epigenetic alterations of the paternal chromatin and the implications suggested by the available literature.

Keywords: DNA methylation; chromatin; embryogenesis; epigenetics; fertilization.

Figures

FIGURE 1
FIGURE 1
Alterations to the epigenome post-fertilization. The top panel illustrates the chromatin structure of the mature sperm immediately following fertilization (highly protaminated with some retension of paternally derived histones). From the following cell is seen the protamine to histone transition where maternally derived histones replace protamines resulting in the decondensation of the sperm head. The middle panel illustrates the various stages of early embryonic development. The bottom panel shows the methylation changes that occur over time in the maternal and paternal pronucleus, where the paternal pronucleus undergoes active demethylation and the maternal DNA is demethylated passively in a replication dependent manner. The approximate chronology of major events in the early embryo is outlined along the bottom of the figure and correlates to the illustrations of embryos above.

References

    1. Abdalla H., Hirabayashi M., Hochi S. (2009a). Demethylation dynamics of the paternal genome in pronuclear-stage bovine zygotes produced by in vitro fertilization and ooplasmic injection of freeze-thawed or freeze-dried spermatozoa. J. Reprod. Dev. 55 433–439
    1. Abdalla H., Yoshizawa Y., Hochi S. (2009b). Active demethylation of paternal genome in mammalian zygotes. J. Reprod. Dev. 55 356–360
    1. Adenot P. G., Szollosi M. S., Geze M., Renard J. P., Debey P. (1991). Dynamics of paternal chromatin changes in live one-cell mouse embryo after natural fertilization. Mol. Reprod. Dev. 28 23–34
    1. Aoki F., Worrad D. M., Schultz R. M. (1997). Regulation of transcriptional activity during the first and second cell cycles in the preimplantation mouse embryo. Dev. Biol. 181 296–307
    1. Aoki V. W., Emery B. R., Liu L., Carrell D. T. (2006a). Protamine levels vary between individual sperm cells of infertile human males and correlate with viability and DNA integrity. J. Androl. 27 890–898
    1. Aoki V. W., Liu L., Jones K. P., Hatasaka H. H., Gibson M., Peterson C. M., Carrell D. T. (2006b). Sperm protamine 1/protamine 2 ratios are related to in vitro fertilization pregnancy rates and predictive of fertilization ability. Fertil. Steril. 86 1408–1415
    1. Arpanahi A., Brinkworth M., Iles D., Krawetz S. A., Paradowska A., Platts A. E., Saida M., Steger K., Tedder P., Miller D. (2009). Endonuclease-sensitive regions of human spermatozoal chromatin are highly enriched in promoter and CTCF binding sequences. Genome Res. 19 1338–1349
    1. Balhorn R. (2007). The protamine family of sperm nuclear proteins. Genome Biol. 8 227
    1. Balhorn R., Reed S., Tanphaichitr N. (1988). Aberrant protamine 1/protamine 2 ratios in sperm of infertile human males. Experientia 44 52–55
    1. Barreto G., Schafer A., Marhold J., Stach D., Swaminathan S. K., Handa V., Döderlein G., Maltry N., Wu W., Lyko F., Niehrs C. (2007). Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445 671–675
    1. Benchaib M., Braun V., Ressnikof D., Lornage J., Durand P., Niveleau A., Guerin J. F. (2005). Influence of global sperm DNA methylation on IVF results. Hum. Reprod. 20 768–773
    1. Bertelsmann H., Kuehbacher M., Weseloh G., Kyriakopoulos A., Behne D. (2007). Sperm nuclei glutathione peroxidases and their occurrence in animal species with cysteine-containing protamines. Biochim. Biophys. Acta 1770 1459–1467
    1. Bhattacharya S. K., Ramchandani S., Cervoni N., Szyf M. (1999). A mammalian protein with specific demethylase activity for mCpG DNA. Nature 397 579–583
    1. Biermann K., Steger K. (2007). Epigenetics in male germ cells. J. Androl. 28 466–480
    1. Bui H. T., Wakayama S., Mizutani E., Park K. K., Kim J. H., Van Thuan N., Wakayama T. (2011). Essential role of paternal chromatin in the regulation of transcriptional activity during mouse preimplantation development. Reproduction 141 67–77
    1. Carrell D. T., Hammoud S. S. (2010). The human sperm epigenome and its potential role in embryonic development. Mol. Hum. Reprod. 16 37–47
    1. Dadoune J. P. (1995). The nuclear status of human sperm cells. Micron 26 323–345
    1. Davis W., Jr., De Sousa P. A., Schultz R. M. (1996). Transient expression of translation initiation factor eIF-4C during the 2-cell stage of the preimplantation mouse embryo: identification by mRNA differential display and the role of DNA replication in zygotic gene activation. Dev. Biol. 174 190–201
    1. Dean W., Santos F., Stojkovic M., Zakhartchenko V., Walter J., Wolf E., Reik W. (2001). Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proc. Natl. Acad. Sci. U.S.A. 98 13734–13738
    1. Doerksen T., Trasler J. M. (1996). Developmental exposure of male germ cells to 5-azacytidine results in abnormal preimplantation development in rats. Biol. Reprod. 55 1155–1162
    1. Evsikov A. V, Marin de Evsikova C. (2009). Gene expression during the oocyte-to-embryo transition in mammals. Mol. Reprod. Dev. 76 805–818
    1. Glaser S., Lubitz S., Loveland K. L., Ohbo K., Robb L., Schwenk F., Seibler J., Roellig D., Kranz A., Anastassiadis K., Stewart A. F. (2009). The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis. Epigenet. Chromatin 2 5
    1. Hajkova P. (2010). Epigenetic reprogramming – taking a lesson from the embryo. Curr. Opin. Cell Biol. 22 342–350
    1. Hales B. F., Grenier L., Lalancette C., Robaire B. (2011). Epigenetic programming: from gametes to blastocyst. Birth Defects Res. A Clin. Mol. Teratol. 91 652–665
    1. Hammoud S. S., Nix D. A., Hammoud A. O., Gibson M., Cairns B. R., Carrell D. T. (2011). Genome-wide analysis identifies changes in histone retention and epigenetic modifications at developmental and imprinted gene loci in the sperm of infertile men. Hum. Reprod. 26 2558–2569
    1. Hammoud S. S., Nix D. A., Zhang H., Purwar J., Carrell D. T., Cairns B. R. (2009). Distinctive chromatin in human sperm packages genes for embryo development. Nature 460 473–478
    1. Hayashi S., Yang J., Christenson L., Yanagimachi R., Hecht N. B. (2003). Mouse preimplantation embryos developed from oocytes injected with round spermatids or spermatozoa have similar but distinct patterns of early messenger RNA expression. Biol. Reprod. 69 1170–1176
    1. Hendrich B., Hardeland U., Ng H. H., Jiricny J., Bird A. (1999). The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature 401 301–304
    1. Henery C. C., Miranda M., Wiekowski M., Wilmut I., DePamphilis M. L. (1995). Repression of gene expression at the beginning of mouse development. Dev. Biol. 169 448–460
    1. Jenkins T. G., Carrell D. T. (2010). The paternal epigenome and embryogenesis: poising mechanisms for development. Asian J. Androl. 13 76–80
    1. Jones E. L., Zalensky A. O., Zalenskaya I. A. (2011). Protamine withdrawal from human sperm nuclei following heterologous ICSI into hamster oocytes. Protein Pept. Lett. 18 811–816
    1. Kageyama S., Nagata M., Aoki F. (2004). Isolation of nascent messenger RNA from mouse preimplantation embryos. Biol. Reprod. 71 1948–1955
    1. Kaneda M., Sado T., Hata K., Okano M., Tsujimoto N., Li E., Sasaki H. (2004). Role of de novo DNA methyltransferases in initiation of genomic imprinting and X-chromosome inactivation. Cold Spring Harb. Symp. Quant. Biol. 69 125–129
    1. Kato Y., Kaneda M., Hata K., Kumaki K., Hisano M., Kohara Y., Okano M., Li E., Nozaki M., Sasaki H. (2007). Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. Hum. Mol. Genet. 16 2272–2280
    1. Kelly T. L., Li E., Trasler J. M. (2003). 5-aza-2′-deoxycytidine induces alterations in murine spermatogenesis and pregnancy outcome. J. Androl. 24 822–830
    1. Kishigami S., Van Thuan N., Hikichi T., Ohta H., Wakayama S., Mizutani E., Wakayama T. (2006). Epigenetic abnormalities of the mouse paternal zygotic genome associated with microinsemination of round spermatids. Dev. Biol. 289 195–205
    1. Krawetz S. A., Kruger A., Lalancette C., Tagett R., Anton E., Draghici S., Diamond M. P. (2011). A survey of small RNAs in human sperm. Hum. Reprod. 26 3401–3412
    1. Lachner M., Jenuwein T. (2002). The many faces of histone lysine methylation. Curr. Opin. Cell Biol. 14 286–298
    1. La Salle S., Oakes C. C., Neaga O. R., Bourc’his D., Bestor T. H., Trasler J. M. (2007). Loss of spermatogonia and wide-spread DNA methylation defects in newborn male mice deficient in DNMT3L. BMC Dev. Biol. 7 104 10.1186/1471-213X-7-104
    1. Lee M. G., Wynder C., Cooch N., Shiekhattar R. (2005). An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437 432–435
    1. Li E. (2002). Chromatin modification and epigenetic reprogramming in mammalian development. Nat. Rev. Genet. 3 662–673
    1. Ma J., Svoboda P., Schultz R. M., Stein P. (2001). Regulation of zygotic gene activation in the preimplantation mouse embryo: global activation and repression of gene expression. Biol. Reprod. 64 1713–1721
    1. Majumder S., Miranda M., DePamphilis M. L. (1993). Analysis of gene expression in mouse preimplantation embryos demonstrates that the primary role of enhancers is to relieve repression of promoters. EMBO J. 12 1131–1140
    1. Mayer W., Niveleau A., Walter J., Fundele R., Haaf T. (2000). Demethylation of the zygotic paternal genome. Nature 403 501–502
    1. McGrath J., Solter D. (1984). Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37 179–183
    1. McLay D. W., Clarke H. J. (2003). Remodelling the paternal chromatin at fertilization in mammals. Reproduction 125 625–633
    1. Meehan R. R. (2003). DNA methylation in animal development. Semin. Cell Dev. Biol. 14 53–65
    1. Metivier R., Gallais R., Tiffoche C., Le Péron C., Jurkowska R. Z., Carmouche R. P., Ibberson D., Barath P., Demay F., Reid G., Benes V., Jeltsch A., Gannon F., Salbert G. (2008). Cyclical DNA methylation of a transcriptionally active promoter. Nature 452 45–50
    1. Morgan H. D., Dean W., Coker H. A., Reik W., Petersen-Mahrt S. K. (2004). Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J. Biol. Chem. 279 52353–52360
    1. Nakamura T., Arai Y., Umehara H., Masuhara M., Kimura T., Taniguchi H., Sekimoto T., Ikawa M., Yoneda Y., Okabe M., Tanaka S., Shiota K., Nakano T. (2007). PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat. Cell Biol. 9 64–71
    1. Nakazawa Y., Shimada A., Noguchi J., Domeki I., Kaneko H., Kikuchi K. (2002). Replacement of nuclear protein by histone in pig sperm nuclei during in vitro fertilization. Reproduction 124 565–572
    1. Nanassy L., Liu L., Griffin J., Carrell D. T. (2011). The clinical utility of the protamine 1/protamine 2 ratio in sperm. Protein Pept. Lett. 18 772–777
    1. Navarro-Costa P., Nogueira P., Carvalho M., Leal F., Cordeiro I., Calhaz-Jorge C., Goncalves J., Plancha C. E. (2010). Incorrect DNA methylation of the DAZL promoter CpG island associates with defective human sperm. Hum. Reprod. 25 2647–2654
    1. Nonchev S., Tsanev R. (1990). Protamine-histone replacement and DNA replication in the male mouse pronucleus. Mol. Reprod. Dev. 25 72–76
    1. Oakes C. C., Kelly T. L., Robaire B., Trasler J. M. (2007). Adverse effects of 5-aza-2′-deoxycytidine on spermatogenesis include reduced sperm function and selective inhibition of de novo DNA methylation. J. Pharmacol. Exp. Ther. 322 1171–1180
    1. Ohnishi Y., Totoki Y., Toyoda A., Watanabe T., Yamamoto Y., Tokunaga K., Sakaki Y., Sasaki H., Hohjoh H. (2010). Small RNA class transition from siRNA/piRNA to miRNA during pre-implantation mouse development. Nucleic Acids Res. 38 5141–5151
    1. Oliva R., Dixon G. H. (1990). Vertebrate protamine gene evolution I. Sequence alignments and gene structure. J. Mol. Evol. 30 333–346
    1. Ostermeier G. C., Dix D. J., Miller D., Khatri P., Krawetz S. A. (2002). Spermatozoal RNA profiles of normal fertile men. Lancet 360 772–777
    1. Ostermeier G. C., Miller D., Huntriss J. D., Diamond M. P., Krawetz S. A. (2004). Reproductive biology: delivering spermatozoan RNA to the oocyte. Nature 429 154
    1. Perreault S. D. (1992). Chromatin remodeling in mammalian zygotes. Mutat. Res. 296 43–55
    1. Perreault S. D., Barbee R. R., Slott V. L. (1988). Importance of glutathione in the acquisition and maintenance of sperm nuclear decondensing activity in maturing hamster oocytes. Dev. Biol. 125 181–186
    1. Pfeifer H., Conrad M., Roethlein D., Kyriakopoulos A., Brielmeier M., Bornkamm G. W., Behne D. (2001). Identification of a specific sperm nuclei selenoenzyme necessary for protamine thiol cross-linking during sperm maturation. FASEB J. 15 1236–1238
    1. Puri D., Dhawan J., Mishra R. K. (2010). The paternal hidden agenda: epigenetic inheritance through sperm chromatin. Epigenetics 5 386–391
    1. Rassoulzadegan M., Grandjean V., Gounon P., Vincent S., Gillot I., Cuzin F. (2006). RNA-mediated non-Mendelian inheritance of an epigenetic change in the mouse. Nature 441 469–474
    1. Razin A., Szyf M., Kafri T., Roll M., Giloh H., Scarpa S., Carotti D., Cantoni G. L. (1986). Replacement of 5-methylcytosine by cytosine: a possible mechanism for transient DNA demethylation during differentiation. Proc. Natl. Acad. Sci. U.S.A. 83 2827–2831
    1. Reik W., Dean W., Walter J. (2001). Epigenetic reprogramming in mammalian development. Science 293 1089–1093
    1. Rodman T. C., Pruslin F. H., Hoffmann H. P., Allfrey V. G. (1981). Turnover of basic chromosomal proteins in fertilized eggs: a cytoimmunochemical study of events in vivo. J. Cell Biol. 90 351–361
    1. Rougier N., Bourc’his D., Gomes D. M., Niveleau A., Plachot M., Paldi A., Viegas-Pequignot E. (1998). Chromosome methylation patterns during mammalian preimplantation development. Genes Dev. 12 2108–2113
    1. Santos F., Hendrich B., Reik W., Dean W. (2002). Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev. Biol. 241 172–182
    1. Shimada A., Kikuchi K., Noguchi J., Akama K., Nakano M., Kaneko H. (2000). Protamine dissociation before decondensation of sperm nuclei during in vitro fertilization of pig oocytes. J. Reprod. Fertil. 120 247–256
    1. Suganuma T., Workman J. L. (2008). Crosstalk among histone modifications. Cell 135 604–607
    1. Surani M. A., Barton S. C., Norris M. L. (1984). Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308 548–550
    1. Sutovsky P., Schatten G. (1997). Depletion of glutathione during bovine oocyte maturation reversibly blocks the decondensation of the male pronucleus and pronuclear apposition during fertilization. Biol. Reprod. 56 1503–1512
    1. Tanphaichitr N., Sobhon P., Taluppeth N., Chalermisarachai P. (1978). Basic nuclear proteins in testicular cells and ejaculated spermatozoa in man. Exp. Cell Res. 117 347–356
    1. Ward W. S., Coffey D. S. (1991). DNA packaging and organization in mammalian spermatozoa: comparison with somatic cells. Biol. Reprod. 44 569–574
    1. Weiss A., Keshet I., Razin A., Cedar H. (1996). DNA demethylation in vitro: involvement of RNA. Cell 86 709–718
    1. Wossidlo M., Arand J., Sebastiano V., Lepikhov K., Boiani M., Reinhardt R., Scholer H., Walter J. (2010). Dynamic link of DNA demethylation, DNA strand breaks and repair in mouse zygotes. EMBO J. 29 1877–1888
    1. Wright S. J., Longo F. J. (1988). Sperm nuclear enlargement in fertilized hamster eggs is related to meiotic maturation of the maternal chromatin. J. Exp. Zool. 247 155–165
    1. Wykes S. M., Krawetz S. A. (2003). The structural organization of sperm chromatin. J. Biol. Chem. 278 29471–29477
    1. Yang Y., Bai W., Zhang L., Yin G., Wang X., Wang J., Zhao H., Han Y., Yao Y. Q. (2008). Determination of microRNAs in mouse preimplantation embryos by microarray. Dev. Dyn. 237 2315–2327
    1. Young L. E., Beaujean N. (2004). DNA methylation in the preimplantation embryo: the differing stories of the mouse and sheep. Anim. Reprod. Sci. 82–83 61–78
    1. Zaitseva I., Zaitsev S., Alenina N., Bader M., Krivokharchenko A. (2007). Dynamics of DNA-demethylation in early mouse and rat embryos developed in vivo and in vitro. Mol. Reprod. Dev. 74 1255–1261

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe