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How could we completely erase the epigenetic marks during cellular reprogramming?

Shubhankar Kulkarni
Shubhankar Kulkarni Jul 27, 2020
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How could we completely erase the epigenetic marks from the cells during reprogramming?

Direct reprogramming (avoiding dedifferentiation and redifferentiation) was shown to preserve the aging phenotype by increasing factors involved in cellular senescence (p53, p21, and p16). Examination of the iPSC methylome showed that they retain donor-age and tissue memory. They have different teratogenic, hematopoietic, and osteogenic potential based on their tissue of origin. Certain CpG sites preserve age-specific methylation pattern even after 100 passages following reprogramming. These findings suggest that reprogramming does not fully bring differentiated cells to their ground state, but rather approximates it.

[1]Mertens J, Paquola ACM, Ku M, Hatch E, Böhnke L, Ladjevardi S, et al. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell [Internet]. 2015 Dec;17(6):705–18. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1934590915004087

[2]Banito A, Rashid ST, Acosta JC, Li S, Pereira CF, Geti I, et al. Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev [Internet]. 2009 Sep 15;23(18):2134–9. Available from: http://genesdev.cshlp.org/cgi/doi/10.1101/gad.1811609

[3]Lo Sardo V, Ferguson W, Erikson GA, Topol EJ, Baldwin KK, Torkamani A. Influence of donor age on induced pluripotent stem cells. Nat Biotechnol [Internet]. 2017 Jan 12;35(1):69–74. Available from: http://www.nature.com/articles/nbt.3749

[4]Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, et al. Epigenetic memory in induced pluripotent stem cells. Nature [Internet]. 2010 Sep 19;467(7313):285–90. Available from: http://www.nature.com/articles/nature09342

[5]Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K, et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol [Internet]. 2009 Aug 9;27(8):743–5. Available from: http://www.nature.com/articles/nbt.1554

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Somatic Memory

Jamila Aug 10, 2020
Repeatedly passaging cells may help to erase the epigenetic marks that cause retention of the somatic memory. iPS cells that were reprogrammed from murine cells had their somatic memory erased after the 20th passage. (https://www.nature.com/articles/nbt.1667) In another study, peripheral blood mononuclear cells (PBMCs) taken from elderly individuals had retained epigenetic marks even after cellular reprogramming. The age-associated epigenetic marks in these PBMCs were successfully reduced after several passages. However, several passages could not remove epigenetic marks in 6 of the 34 sites. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505172/) Therefore; passaging cells after cellular reprogramming can reduce epigenetic marks in murine cells and human cells but may not remove all the epigenetic marks. The maturity of the cell can also impact the retention of memory. For example, immature bone marrow cells were more likely to keep their somatic memory compared to the late-stage bone marrow cells. This is because early-stage cells were more likely to differentiate into the cell of their natural origin. (https://www.liebertpub.com/doi/10.1089/scd.2011.0010) Therefore, mature cells retain less somatic memory when reprogrammed. However, immature cells usually have higher reprogramming efficiency compared to mature cells. (https://europepmc.org/article/med/32016780) The method used to conduct cellular reprogramming may be able to erase epigenetic marks. Epigenetic patterns were retained when conducting cellular reprogramming with transcription factors. However, this was not observed when the same cells were reprogrammed using somatic cell nuclear transfer. (https://www.nature.com/articles/nature13551) Therefore, in order to prevent the retention of somatic memory, alternative methods of reprogramming should be researched. The usage of 5-azacytidine and trichostatin A after cellular reprogramming was able to reduce the somatic memory of iPS cells. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150836/) There are several other small molecules similar to 5-azacytidine and trichostatin A that have an impact on epigenetic patterns. (https://www.eurekaselect.com/node/183001/article/advances-in-small-molecules-in-cellular-reprogramming-effects-structures-and-mechanisms) Therefore, I wonder if cellular reprogramming was conducted with the use of small molecules instead of the OKSM factors would that make a difference to the epigenetic marks and thus the retention of somatic memory?
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