Reprogramming

Reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian 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 once again demethylated and remethylated (except for differentially methylated regions associated with imprinted genes). This reprogramming is likely required for totipotency of the newly formed embryo and erasure of acquired epigenetic changes. In vitro manipulation of pre-implantation embryos has been shown to disrupt methylation patterns at imprinted loci and plays a crucial role in cloned animals.

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.

History

The first person to successfully demonstrate reprogramming was Sir 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. For this achievement he received the 2012 Nobel Prize in Medicine alongside Shinya Yamanaka.[1] Dr. Yamanaka was the first to demonstrate that this somatic cell nuclear transfer or oocyte-based reprogramming process (see below), that Dr. Gurdon discovered, could be recapitulated by defined factors (Oct4, Sox2, Klf4, and c-Myc) to generate induced pluripotent stem cells (iPSCs).[2] Other combinations of genes have also been used.[3]

Drs Ian Wilmut and Keith Campbell were the first to demonstrate that an adult mammalian cell could be reprogrammed back into a pluripotent state when they cloned Dolly the sheep in 1997.

Variability

The properties of cells obtained after reprogramming can vary significantly, in particular among iPSCs.[4] 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.[4]

Somatic cell nuclear transfer

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 (see also: cloning)

Reprogramming is distinct from development of a somatic epitype, as somatic epitypes can potentially be altered after an organism has left the developmental stage of life.

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

References

  1. ↑ "The Nobel Prize in Physiology or Medicine – 2012 Press Release". Nobel Media AB. 8 October 2012.
  2. ↑ Takahashi, K.; Yamanaka, S. (2006). "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors". Cell. 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. PMID 16904174.
  3. ↑ Baker, Monya (2007-12-06). "Adult cells reprogrammed to pluripotency, without tumors". Nature Reports Stem Cells. doi:10.1038/stemcells.2007.124. Retrieved 2007-12-11.
  4. 1 2 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, et al. (3 August 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.
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  2. ^ 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". Biol. Reprod. 69 (3): 902–14. doi:10.1095/biolreprod.103.017293. PMID 12748125. 
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  4. ^ Gurdon JB (December 1962). "The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles". J Embryol Exp Morphol. 10: 622–40. 
  5. ^ Hochedlinger K, Jaenisch R (June 2006). "Nuclear reprogramming and pluripotency" (PDF). Nature. 441 (7097): 1061–7. doi:10.1038/nature04955. PMID 16810240. (Review)
  6. ^ 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. 
  7. ^ Mathers JC (June 2006). "Nutritional modulation of ageing: genomic and epigenetic approaches". Mech. Ageing Dev. 127 (6): 584–9. doi:10.1016/j.mad.2006.01.018. PMID 16513160. 


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