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Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming [RRBS]

ABSTRACT: Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming [RRBS]

PROVIDER: PRJNA658342 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12483700_1.fastq.gz	Fastqsanger.gz
	SRR12483700_2.fastq.gz	Fastqsanger.gz
	SRR12483701_1.fastq.gz	Fastqsanger.gz
	SRR12483701_2.fastq.gz	Fastqsanger.gz
	SRR12483702_1.fastq.gz	Fastqsanger.gz

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Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming [RRBS]

Project description:The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can transform somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Transient OSKM expression perturbs cellular homeostasis in a reversible manner and cycles of such incomplete reprogramming rejuvenate features of aging in cells and progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression in all tissues. We found that this manipulation is sufficient to rejuvenate a substantial fraction of the DNA methylation changes in gene regulatory elements that occur upon aging in the pancreas, liver and spleen. Similarly, we observed rejuvenation at the transcriptomic level, especially regarding biological processes known to change during aging. Finally, a subset of serum metabolites normally altered with aging were restored to young levels upon reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum.

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Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

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Project description: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. 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.

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