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, Jahnvi Pflueger, Thomas Frazer, Dulce B. Vargas-Landín, Jacob M. Paynter, Nathan Smits, Ning Liu, John F. Ouyang, Fernando J. Rossello, Hun S. Chy, Owen J. L. Rackham, Andrew L. Laslett, James Breen, Geoffrey J. Faulkner, Christian M. Nefzger, Jose M. Polo () and Ryan Lister ()
Additional contact information
Sam Buckberry: Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia
Xiaodong Liu: Monash University
Daniel Poppe: Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia
Jia Ping Tan: Monash University
Guizhi Sun: Monash University
Joseph Chen: Monash University
Trung Viet Nguyen: Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia
Alex de Mendoza: Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia
Jahnvi Pflueger: Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia
Thomas Frazer: Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia
Dulce B. Vargas-Landín: Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia
Jacob M. Paynter: Monash University
Nathan Smits: University of Queensland
Ning Liu: South Australian Health and Medical Research Institute
John F. Ouyang: Duke–National University of Singapore Medical School
Fernando J. Rossello: Monash University
Hun S. Chy: Monash University
Owen J. L. Rackham: Duke–National University of Singapore Medical School
Andrew L. Laslett: Monash University
James Breen: Australian National University
Geoffrey J. Faulkner: University of Queensland
Christian M. Nefzger: Monash University
Jose M. Polo: Monash University
Ryan Lister: Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia

Nature, 2023, vol. 620, issue 7975, 863-872

Abstract: 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.

Date: 2023
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06424-7 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:620:y:2023:i:7975:d:10.1038_s41586-023-06424-7

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06424-7

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().