Transient naive reprogramming corrects hiPS cells functionally and epigenetically

Sam Buckberry, Xiaodong Liu, Daniel Poppe, Jia Ping Tan, Guizhi Sun, Joseph Chen, Trung Viet Nguyen, Alex de Mendoza Soler, Jahnvi Pflueger, Thomas Frazer, Dulce Vargas Landin, Jacob M Paynter, Nathan Smits, Ning Liu, John F Ouyang, Fernando J Rossello, Hun S. Chy, Owen J L Rackham, Andrew L. Laslett, James BreenGeoffrey J. Faulkner, Christian M Nefzger, Jose M Polo, Ryan Lister

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)863-872
Number of pages10
JournalNature
Volume620
Issue number7975
DOIs
Publication statusPublished - 24 Aug 2023

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