The reprogramming of somatic cells into different lineages by transdifferentiation holds great promise for regenerative medicine and replacement therapies. However, a recent report by Radwan et al. (PNAS, 2024) finds that transdifferentiated cells fail to fully adopt the DNA methylation profiles of their new lineage. This has important implications regarding the viability of transdifferentiation as a strategy for cell replacement therapy.
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References
1.
BellCC, FaulknerGJ, GilanO. Chromatin-based memory as a self-stabilizing influence on cell identity. Genome Biol, 2024; 25(1):320; doi: 10.1186/s13059-024-03461-x
2.
Cieślar-PobudaA, KnoflachV, RinghMV, et al.Transdifferentiation and reprogramming: Overview of the processes, their similarities and differences. Biochim Biophys Acta Mol Cell Res, 2017; 1864(7):1359–1369; doi: 10.1016/j.bbamcr.2017.04.017
3.
FiczG, HoreTA, SantosF, et al.FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell, 2013; 13(3):351–359; doi: 10.1016/j.stem.2013.06.004
4.
HonGC, RajagopalN, ShenY, et al.Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues. Nat Genet, 2013; 45(10):1198–1206; doi: 10.1038/ng.2746
5.
JalvingM, SchepersH. Induced pluripotent stem cells: Will they be safe? Curr Opin Mol Ther, 2009; 11(4):383–393.
6.
KreibichE, KleinendorstR, BarzaghiG, et al.Single-molecule footprinting identifies context-dependent regulation of enhancers by DNA methylation. Mol Cell, 2023; 83(5):787–802.e9; doi: 10.1016/j.molcel.2023.01.017
7.
LuoC, LeeQY, WapinskiO, et al.Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons. Elife, 2019; 8; doi: 10.7554/eLife.40197
8.
MerrellAJ, PengT, LiJ, et al.Dynamic transcriptional and epigenetic changes drive cellular plasticity in the liver. Hepatology, 2021; 74(1):444–457; doi: 10.1002/hep.31704
9.
PopRT, PisanteA, NagyD, et al.Identification of mammalian transcription factors that bind to inaccessible chromatin. Nucleic Acids Res, 2023; 51(16):8480–8495; doi: 10.1093/nar/gkad614
10.
RadwanA, EcclestonJ, SabagO, et al.Transdifferentiation occurs without resetting development-specific DNA methylation, a key determinant of full-function cell identity. Proc Natl Acad Sci USA, 2024; 121(39):e2411352121; doi: 10.1073/pnas.2411352121
11.
Rodríguez-UbrevaJ, CiudadL, Gómez-CabreroD, et al.Pre-B cell to macrophage transdifferentiation without significant promoter DNA methylation changes. Nucleic Acids Res, 2012; 40(5):1954–1968; doi: 10.1093/nar/gkr1015
12.
TakahashiK, YamanakaS. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006; 126(4):663–676; doi: 10.1016/j.cell.2006.07.024
13.
TapscottSJ, DavisRL, ThayerMJ, et al.MyoD1: A nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science, 1988; 242(4877):405–411; doi: 10.1126/science.3175662
14.
WangH, YangY, LiuJ, et al.Direct cell reprogramming: Approaches, mechanisms and progress. Nat Rev Mol Cell Biol, 2021; 22(6):410–424; doi: 10.1038/s41580-021-00335-z
15.
YagiM, JiF, CharltonJ, et al.Dissecting dual roles of MyoD during lineage conversion to mature myocytes and myogenic stem cells. Genes Dev, 2021; 35(17–18):1209–1228; doi: 10.1101/gad.348678.121
