Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/140035
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Type: | Journal article |
Title: | Transient naive reprogramming corrects hiPS cells functionally and epigenetically |
Author: | Buckberry, S. Liu, X. Poppe, D. Tan, J.P. Sun, G. Chen, J. Nguyen, T.V. de Mendoza, A. Pflueger, J. Frazer, T. Vargas-Landín, D.B. Paynter, J.M. Smits, N. Liu, N. Ouyang, J.F. Rossello, F.J. Chy, H.S. Rackham, O.J.L. Laslett, A.L. Breen, J. et al. |
Citation: | Nature, 2023; 620(7975):863-872 |
Publisher: | Springer Science and Business Media LLC |
Issue Date: | 2023 |
ISSN: | 0028-0836 1476-4687 |
Statement of Responsibility: | Sam Buckberry ... Jose M. Polo ... Jimmy Breen ... Ning Liu ... et al. |
Abstract: | Cells undergo a major epigenome reconfiguration when reprogrammed to human induced pluripotent stem cells (hiPS cells). However, the epigenomes of hiPS cells and human embryonic stem (hES) cells differ significantly, which affects hiPS cell function1-8. These differences include epigenetic memory and aberrations that emerge during reprogramming, for which the mechanisms remain unknown. Here we characterized the persistence and emergence of these epigenetic differences by performing genome-wide DNA methylation profiling throughout primed and naive reprogramming of human somatic cells to hiPS cells. We found that reprogramming-induced epigenetic aberrations emerge midway through primed reprogramming, whereas DNA demethylation begins early in naive reprogramming. Using this knowledge, we developed a transient-naive-treatment (TNT) reprogramming strategy that emulates the embryonic epigenetic reset. We show that the epigenetic memory in hiPS cells is concentrated in cell of origin-dependent repressive chromatin marked by H3K9me3, lamin-B1 and aberrant CpH methylation. TNT reprogramming reconfigures these domains to a hES cell-like state and does not disrupt genomic imprinting. Using an isogenic system, we demonstrate that TNT reprogramming can correct the transposable element overexpression and differential gene expression seen in conventional hiPS cells, and that TNT-reprogrammed hiPS and hES cells show similar differentiation efficiencies. Moreover, TNT reprogramming enhances the differentiation of hiPS cells derived from multiple cell types. Thus, TNT reprogramming corrects epigenetic memory and aberrations, producing hiPS cells that are molecularly and functionally more similar to hES cells than conventional hiPS cells. We foresee TNT reprogramming becoming a new standard for biomedical and therapeutic applications and providing a novel system for studying epigenetic memory. |
Keywords: | Epigenetic memory; Epigenomics; Reprogramming |
Rights: | © The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
DOI: | 10.1038/s41586-023-06424-7 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1069830 http://purl.org/au-research/grants/nhmrc/1178460 http://purl.org/au-research/grants/arc/LE170100225 http://purl.org/au-research/grants/arc/FT180100674 http://purl.org/au-research/grants/nhmrc/1104560 http://purl.org/au-research/grants/nhmrc/1111206 http://purl.org/au-research/grants/arc/1111206 http://purl.org/au-research/grants/nhmrc/1173711 |
Published version: | http://dx.doi.org/10.1038/s41586-023-06424-7 |
Appears in Collections: | Medicine publications |
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hdl_140035.pdf | Published version | 69.62 MB | Adobe PDF | View/Open |
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