Gene Resistance to Transcriptional Reprogramming following Nuclear Transfer Is Directly Mediated by Multiple Chromatin-Repressive Pathways
Elsevier (Cell Press)
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Jullien, J., Vodnala, M., Pasque, V., Oikawa, M., Miyamoto, K., Allen, G., David, S., et al. (2017). Gene Resistance to Transcriptional Reprogramming following Nuclear Transfer Is Directly Mediated by Multiple Chromatin-Repressive Pathways. Molecular Cell, 65 (5), 873-884.e8. https://doi.org/10.1016/j.molcel.2017.01.030
Understanding the mechanism of resistance of genes to reactivation will help improve the success of nuclear reprogramming. Using mouse embryonic fibroblast nuclei with normal or reduced DNA methylation in combination with chromatin modifiers able to erase H3K9me3, H3K27me3, and H2AK119ub1 from transplanted nuclei, we reveal the basis for resistance of genes to transcriptional reprogramming by oocyte factors. A majority of genes is affected by more than one type of treatment, suggesting that resistance can require repression through multiple epigenetic mechanisms. We classify resistant genes according to their sensitivity to 11 chromatin modifier combinations, revealing the existence of synergistic as well as adverse effects of chromatin modifiers on removal of resistance. We further demonstrate that the chromatin modifier USP21 reduces resistance through its H2AK119 deubiquitylation activity. Finally, we provide evidence that H2A ubiquitylation also contributes to resistance to transcriptional reprogramming in mouse nuclear transfer embryos.
transcriptional reprogramming, oocyte, xenopus, nuclear transfer, resistance, epigenetic, chromatin
This work is funded by grants from the Wellcome Trust (101050/Z/13/Z) and the MRC (MR/K011022/1) and supported by the Gurdon Institute core grant from Cancer Research UK (C6946/A14492) and the Wellcome Trust (092096/Z/10/Z). This research was supported in part by the Intramural Research Program of NIAMS at the NIH (1Z01AR041126-17). M.V. was supported by a Svenska Sällskapet för Medicinsk Forskning (SSMF) postdoctoral fellowship. S.W. was supported in part by fellowships from the Gates Cambridge Trust and NIH-Cambridge MD/PhD Program (T32GM007367). M.O. was supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science (JSPS). K.M. is supported by Human Frontier Science Program (RGP0021/2016), JSPS KAKENHI grants JP16H01321 and JP16H01222, and by a Grant for Basic Science Research Projects from The Sumitomo Foundation (150810). V.P. was supported by the Wellcome Trust (081277), the Wallonia-Brussels International Excellence Grant, The Research Foundation – Flanders (FWO) (Odysseus Return Grant G0F7716N), the KU Leuven Research Fund (BOFZAP starting grant StG/15/021BF, C1 grant C14/16/077, and project financing).
Wellcome Trust (092096/Z/10/Z)
Wellcome Trust (101050/Z/13/Z)
Cancer Research UK (A14492)
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External DOI: https://doi.org/10.1016/j.molcel.2017.01.030
This record's URL: https://www.repository.cam.ac.uk/handle/1810/263488
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