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Multi-omic rejuvenation of human cells by maturation phase transient reprogramming

View ORCID ProfileDiljeet Gill, View ORCID ProfileAled Parry, Fátima Santos, View ORCID ProfileIrene Hernando-Herraez, View ORCID ProfileThomas M. Stubbs, View ORCID ProfileInês Milagre, Wolf Reik
doi: https://doi.org/10.1101/2021.01.15.426786
Diljeet Gill
1Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK
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Aled Parry
1Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK
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Fátima Santos
1Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK
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Irene Hernando-Herraez
1Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK
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Thomas M. Stubbs
2Chronomics Limited, 1 St James Court, Norwich NR3 1RU, UK
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Inês Milagre
3Laboratory for Epigenetic Mechanisms/Chromosome Dynamics Lab, Instituto Gulbenkian de Ciência, Portugal
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  • For correspondence: imilagre@igc.gulbenkian.pt wolf.reik@babraham.ac.uk
Wolf Reik
1Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK
4Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
5Centre for Trophoblast Research, University of Cambridge, Cambridge, CB2 3EG, UK
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  • For correspondence: imilagre@igc.gulbenkian.pt wolf.reik@babraham.ac.uk
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Abstract

Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first “maturation phase transient reprogramming” (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells reacquire their fibroblast identity following MPTR, possibly as a result of persisting epigenetic memory at enhancers. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR is substantially greater than that achieved in previous transient reprogramming protocols. MPTR fibroblasts produced youthful levels of collagen proteins, suggesting functional rejuvenation. Overall, our work demonstrates that it is possible to separate rejuvenation from pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.

Highlights

  • We developed a novel method by which human fibroblasts are reprogrammed until the maturation phase of iPSCs and are then returned to fibroblast identity

  • DNA methylation memory in fibroblast enhancers may allow recovery of cell identity when fibroblast gene expression programmes are already extinct

  • Molecular measures of ageing including transcriptome and DNA methylation clocks and H3K9me3 levels reveal robust and substantial rejuvenation

  • Functional rejuvenation of fibroblasts by MPTR is suggested by reacquisition of youthful levels of collagen proteins

Competing Interest Statement

W.R. is a consultant and shareholder of Cambridge Epigenetix. T.S. is CEO and shareholder of Chronomics. All other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 17, 2021.
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Multi-omic rejuvenation of human cells by maturation phase transient reprogramming
Diljeet Gill, Aled Parry, Fátima Santos, Irene Hernando-Herraez, Thomas M. Stubbs, Inês Milagre, Wolf Reik
bioRxiv 2021.01.15.426786; doi: https://doi.org/10.1101/2021.01.15.426786
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Multi-omic rejuvenation of human cells by maturation phase transient reprogramming
Diljeet Gill, Aled Parry, Fátima Santos, Irene Hernando-Herraez, Thomas M. Stubbs, Inês Milagre, Wolf Reik
bioRxiv 2021.01.15.426786; doi: https://doi.org/10.1101/2021.01.15.426786

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