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In biology, reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development or in cell culture.[1] Such control is also often associated with alternative covalent modifications of histones.

DNA methylation patterns are largely erased and then re-established between generations in mammals. Almost all of the methylations from the parents are erased, first during gametogenesis, and again in early embryogenesis, with demethylation and remethylation occurring each time. Demethylation of early embryogenesis occurs in the preimplantation period in two stages – initially in the zygote, then the first few embryonic replication cycles of morula and blastula. A wave of methylation then takes place during the implantation stage of the embryo, with CpG islands protected from methylation. This results in global repression and allows housekeeping genes to be expressed in all cells. In the post-implantation stage, methylation patterns are stage- and tissue-specific with changes that would define each individual cell type lasting stably over a long time.[2]

Embryonic development[edit]

DNA methylation dynamic during mouse embryonic development

After fertilization some cells of the newly formed embryo migrate to the germinal ridge and will eventually become the germ cells (sperm and oocytes). Due to the phenomenon of genomic imprinting, maternal and paternal genomes are differentially marked and must be properly reprogrammed every time they pass through the germline. Therefore, during the process of gametogenesis the primordial germ cells must have their original biparental DNA methylation patterns erased and re-established based on the sex of the transmitting parent.

After fertilization, the paternal and maternal genomes are demethylated in order to erase their epigenetic signatures and acquire totipotency. There is asymmetry at this point: the male pronucleus undergoes a quick and active demethylation meanwhile the female pronucleus is demethylated passively during consecutive cell divisions. The process of DNA demethylation involves base excision repair and likely other DNA-repair-based mechanisms.[3] Despite the global nature of this process, there are certain sequences that get to avoid it, as differentially methylated regions (DMRS) associated with imprinted genes, retrotransposons and centromeric heterochromatin. Remethylation is needed again to differentiate the embryo into a complete organism.[4]

In vitro manipulation of pre-implantation embryos has been shown to disrupt methylation patterns at imprinted loci[5] and plays a crucial role in cloned animals.[6]

In cell culture systems[edit]

Reprogramming can also be induced artificially through the introduction of exogenous factors, usually transcription factors. In this context, it often refers to the creation of induced pluripotent stem cells from mature cells such as adult fibroblasts. This allows the production of stem cells for biomedical research, such as research into stem cell therapies, without the use of embryos. It is carried out by the transfection of stem-cell associated genes into mature cells using viral vectors such as retroviruses.


The first person to successfully demonstrate reprogramming was John Gurdon, who in 1962 demonstrated that differentiated somatic cells could be reprogrammed back into an embryonic state when he managed to obtain swimming tadpoles following the transfer of differentiated intestinal epithelial cells into enucleated frog eggs.[7] For this achievement he received the 2012 Nobel Prize in Medicine alongside Shinya Yamanaka.[8] Yamanaka was the first to demonstrate (in 2006) that this somatic cell nuclear transfer or oocyte-based reprogramming process (see below), that Gurdon discovered, could be recapitulated (in mice) by defined factors (Oct4, Sox2, Klf4, and c-Myc) to generate induced pluripotent stem cells (iPSCs).[9] Other combinations of genes have also been used.[10]


The properties of cells obtained after reprogramming can vary significantly, in particular among iPSCs.[11] Factors leading to variation in the performance of reprogramming and functional features of end products include genetic background, tissue source, reprogramming factor stoichiometry and stressors related to cell culture.[11]

Somatic cell nuclear transfer[edit]

An oocyte can reprogram an adult nucleus into an embryonic state after somatic cell nuclear transfer, so that a new organism can be developed from such cell.[12]

Reprogramming is distinct from development of a somatic epitype,[13] as somatic epitypes can potentially be altered after an organism has left the developmental stage of life.[14] During somatic cell nuclear transfer, the oocyte turns off tissue specific genes in the Somatic cell nucleus and turns back on embryonic specific genes.

See also[edit]


  1. ^ Reik W, Dean W, Walter J (August 2001). "Epigenetic reprogramming in mammalian development". Science (Review). 293 (5532): 1089–93. doi:10.1126/science.1063443. PMID 11498579.
  2. ^ Cedar H, Bergman Y (July 2012). "Programming of DNA methylation patterns". Annual Review of Biochemistry. 81: 97–117. doi:10.1146/annurev-biochem-052610-091920. PMID 22404632.
  3. ^ Ladstätter S, Tachibana-Konwalski K (December 2016). "A Surveillance Mechanism Ensures Repair of DNA Lesions during Zygotic Reprogramming". Cell. 167 (7): 1774–1787.e13. doi:10.1016/j.cell.2016.11.009. PMC 5161750. PMID 27916276.
  4. ^ Seisenberger S, Peat JR, Hore TA, Santos F, Dean W, Reik W (January 2013). "Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 368 (1609): 20110330. doi:10.1098/rstb.2011.0330. PMC 3539359. PMID 23166394.
  5. ^ Mann MR, Chung YG, Nolen LD, Verona RI, Latham KE, Bartolomei MS (September 2003). "Disruption of imprinted gene methylation and expression in cloned preimplantation stage mouse embryos". Biology of Reproduction. 69 (3): 902–14. doi:10.1095/biolreprod.103.017293. PMID 12748125.
  6. ^ Wrenzycki C, Niemann H (December 2003). "Epigenetic reprogramming in early embryonic development: effects of in-vitro production and somatic nuclear transfer". Review. Reproductive Biomedicine Online. 7 (6): 649–56. doi:10.1016/s1472-6483(10)62087-1. PMID 14748963.
  7. ^ Gurdon JB (December 1962). "The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles". Journal of Embryology and Experimental Morphology. 10: 622–40. PMID 13951335.
  8. ^ "The Nobel Prize in Physiology or Medicine – 2012 Press Release". Nobel Media AB. 8 October 2012.
  9. ^ Takahashi K, Yamanaka S (August 2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors" (PDF). Cell. 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. PMID 16904174.
  10. ^ Baker M (2007-12-06). "Adult cells reprogrammed to pluripotency, without tumors". Nature Reports Stem Cells. doi:10.1038/stemcells.2007.124.
  11. ^ a b Paull D, Sevilla A, Zhou H, Hahn AK, Kim H, Napolitano C, Tsankov A, Shang L, Krumholz K, Jagadeesan P, Woodard CM, Sun B, Vilboux T, Zimmer M, Forero E, Moroziewicz DN, Martinez H, Malicdan MC, Weiss KA, Vensand LB, Dusenberry CR, Polus H, Sy KT, Kahler DJ, Gahl WA, Solomon SL, Chang S, Meissner A, Eggan K, Noggle SA (September 2015). "Automated, high-throughput derivation, characterization and differentiation of induced pluripotent stem cells". Nature Methods. 12 (9): 885–92. doi:10.1038/nmeth.3507. PMID 26237226.
  12. ^ Hochedlinger K, Jaenisch R (June 2006). "Nuclear reprogramming and pluripotency". Nature. 441 (7097): 1061–7. doi:10.1038/nature04955. PMID 16810240.
  13. ^ Lahiri DK, Maloney B (2006). "Genes are not our destiny: the somatic epitype bridges between the genotype and the phenotype". Nature Reviews Neuroscience. 7 (12). doi:10.1038/nrn2022-c1.
  14. ^ Mathers JC (June 2006). "Nutritional modulation of ageing: genomic and epigenetic approaches". Mechanisms of Ageing and Development. 127 (6): 584–9. doi:10.1016/j.mad.2006.01.018. PMID 16513160.