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dc.contributor.authorGill, Diljeet
dc.contributor.authorParry, Aled
dc.contributor.authorSantos, Fátima
dc.contributor.authorOkkenhaug, Hanneke
dc.contributor.authorTodd, Christopher D
dc.contributor.authorHernando-Herraez, Irene
dc.contributor.authorStubbs, Thomas M
dc.contributor.authorMilagre, Inês
dc.contributor.authorReik, Wolf
dc.date.accessioned2022-05-10T01:02:10Z
dc.date.available2022-05-10T01:02:10Z
dc.date.issued2022-04-08
dc.identifier.issn2050-084X
dc.identifier.other35390271
dc.identifier.otherPMC9023058
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/336968
dc.descriptionFunder: Milky Way Research Foundation
dc.descriptionFunder: Biotechnology and Biological Sciences Research Council
dc.description.abstractAgeing 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. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of somatic cell reprogramming, which suggests full 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reprogramming" (MPTR) method, where reprogramming factors are selectively expressed until this rejuvenation point then withdrawn. Applying MPTR to dermal fibroblasts from middle-aged donors, we found that cells temporarily lose and then reacquire their fibroblast identity, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. 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 was rejuvenated to a similar extent, including H3K9me3 levels and the DNA methylation ageing clock. The magnitude of rejuvenation instigated by MPTR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.
dc.languageeng
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101579614
dc.sourceessn: 2050-084X
dc.subjectHuman
dc.subjectGenetics
dc.subjectTranscription
dc.subjectAgeing
dc.subjectDNA methylation
dc.subjectRejuvenation
dc.subjectGenomics
dc.subjectReprogramming
dc.subjectStem Cells
dc.subjectRegenerative Medicine
dc.subjectFibroblasts
dc.subjectHumans
dc.subjectDNA Methylation
dc.subjectMiddle Aged
dc.subjectInduced Pluripotent Stem Cells
dc.subjectEpigenomics
dc.subjectCellular Reprogramming
dc.subjectEpigenome
dc.titleMulti-omic rejuvenation of human cells by maturation phase transient reprogramming.
dc.typeArticle
dc.date.updated2022-05-10T01:02:09Z
prism.publicationNameeLife
prism.volume11
dc.identifier.doi10.17863/CAM.84391
rioxxterms.versionofrecord10.7554/elife.71624
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidGill, Diljeet [0000-0002-5725-2466]
dc.contributor.orcidParry, Aled [0000-0001-5192-3727]
dc.contributor.orcidSantos, Fátima [0000-0002-3854-4084]
dc.contributor.orcidOkkenhaug, Hanneke [0000-0003-0669-4069]
dc.contributor.orcidTodd, Christopher D [0000-0003-2663-6173]
dc.contributor.orcidHernando-Herraez, Irene [0000-0003-1193-8419]
dc.contributor.orcidStubbs, Thomas M [0000-0002-2990-7381]
dc.contributor.orcidMilagre, Inês [0000-0003-4753-5523]
dc.contributor.orcidReik, Wolf [0000-0003-0216-9881]
pubs.funder-project-idWellcome Trust (215912/Z/19/Z)
pubs.funder-project-idWellcome Investigator award (210754/Z/18/Z)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International