Non-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells
Butcher, Lee M
Morris, Tiffany J
Soares, Filipa AC
Nature Publishing Group
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Butcher, L. M., Ito, M., Brimpari, M., Morris, T. J., Soares, F. A., Ährlund-Richter, L., Carey, N., et al. (2016). Non-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells. Nature Communications, 7 (10458)https://doi.org/10.1038/ncomms10458
Non-CG methylation is an unexplored epigenetic hallmark of pluripotent stem cells. Here we report that a reduction in non-CG methylation is associated with impaired differentiation capacity into endodermal lineages. Genome-wide analysis of 2,670 non-CG sites in a discovery cohort of 25 phenotyped human induced pluripotent stem cell (hiPSC) lines revealed unidirectional loss (Δβ=13%, P<7.4 × 10−4) of non-CG methylation that correctly identifies endodermal differentiation capacity in 23 out of 25 (92%) hiPSC lines. Translation into a simplified assay of only nine non-CG sites maintains predictive power in the discovery cohort (Δβ=23%, P<9.1 × 10−6) and correctly identifies endodermal differentiation capacity in nine out of ten pluripotent stem cell lines in an independent replication cohort consisting of hiPSCs reprogrammed from different cell types and different delivery systems, as well as human embryonic stem cell (hESC) lines. This finding infers non-CG methylation at these sites as a biomarker when assessing endodermal differentiation capacity as a readout.
biological sciences, developmental biology, molecular biology
We thank Kerra Pearce (UCL Genomics) for array processing, and Tim Fell and Jonathan Best (CellCentric), Jason Wray (UCL) and Rosemary Drake (TAP Biosystems) for discussions. We also thank Minal Patel, Chris Kirton, Anja Kolb-Kokocinski, Willem H. Ouwehand, Richard Durbin and Fiona M. Watt on behalf of the Human Induced Pluripotent Stem Cell Initiative (HipSci) funded by grant WT098503 from the Wellcome Trust and the Medical Research Council, for sharing data and materials. This work was supported in part by a TSB/EPSRC grant (TS/H000933/1). The Vallier lab is supported by the Cambridge Hospitals National Institute for Health Research Biomedical Research Center and an ERC Starting Grant (Relieve IMDS). F.A.C.S. is funded by a PhD studentship from Fundação para a Ciência e a Tecnologia (SFRH/BD/69033/2010). The Ferguson-Smith lab is supported by grants from the MRC and Wellcome Trust, and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510). The Beck lab is supported by the Wellcome Trust (084071), a Royal Society Wolfson Research Merit Award (WM100023), and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510).
External DOI: https://doi.org/10.1038/ncomms10458
This record's URL: https://www.repository.cam.ac.uk/handle/1810/254191
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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