The Ink4/Arf locus is a barrier for iPS cell reprogramming
Open accessAbstract
The mechanisms involved in the reprogramming of differentiated cells into induced pluripotent stem (iPS) cells by the three transcription factors Oct4 (also known as Pou5f1), Klf4 and Sox2 remain poorly understood. The Ink4/Arf locus comprises the Cdkn2a-Cdkn2b genes encoding three potent tumour suppressors, namely p16(Ink4a), p19(Arf) and p15(Ink4b), which are basally expressed in differentiated cells and upregulated by aberrant mitogenic signals. Here we show that the locus is completely silenced in iPS cells, as well as in embryonic stem (ES) cells, acquiring the epigenetic marks of a bivalent chromatin domain, and retaining the ability to be reactivated after differentiation. Cell culture conditions during reprogramming enhance the expression of the Ink4/Arf locus, further highlighting the importance of silencing the locus to allow proliferation and reprogramming. Indeed, the three factors together repress the Ink4/Arf locus soon after their expression and concomitant with the appearance of the first molecular markers of 'stemness'. This downregulation also occurs in cells carrying the oncoprotein large-T, which functionally inactivates the pathways regulated by the Ink4/Arf locus, thus indicating that the silencing of the locus is intrinsic to reprogramming and not the result of a selective process. Genetic inhibition of the Ink4/Arf locus has a profound positive effect on the efficiency of iPS cell generation, increasing both the kinetics of reprogramming and the number of emerging iPS cell colonies. In murine cells, Arf, rather than Ink4a, is the main barrier to reprogramming by activation of p53 (encoded by Trp53) and p21 (encoded by Cdkn1a); whereas, in human fibroblasts, INK4a is more important than ARF. Furthermore, organismal ageing upregulates the Ink4/Arf locus and, accordingly, reprogramming is less efficient in cells from old organisms, but this defect can be rescued by inhibiting the locus with a short hairpin RNA. All together, we conclude that the silencing of Ink4/Arf locus is rate-limiting for reprogramming, and its transient inhibition may significantly improve the generation of iPS cells.
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In vitro, cellular senescence is a potent cell-autonomous barrier to OSKM transcription factor-mediated reprogramming, similar to its tumour suppressor role.
“In vitro studies demonstrated that cellular senescence is a potent cell-autonomous barrier for transcription factor-mediated reprograming using OCT4, SOX2, KLF4 and MYC (commonly referred to as OSKM), in a manner similar to its role in tumour suppression181–183.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [183]
The paper’s main text (indexed under Abstract; page unavailable) reports that loss of Ink4a/Arf improves reprogramming, including when c-Myc is added to Oct4, Sox2 and Klf4. Its concluding passage draws a parallel between the locus’s roles as a barrier to malignancy and to de-differentiation. The experiments establish a barrier involving this senescence-associated locus, but do not directly demonstrate that cellular senescence itself is the cell-autonomous barrier claimed. (LLM, conf=0.82)
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- Authors
- Li, H., Collado, M., Villasante, A., Strati, K., Ortega, S., Cañamero, M., Blasco, M. A., & Serrano, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Serrano, Manuel
- Venue
- Nature
- Published
- 2009-08
- Volume
- 460
- Issue
- 7259
- Pages
- 1136-1139
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3578184
- OpenAlex
- W2076047032
- Cited by
- 968
- References
- 31
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 11 · 2023: 23 · 2022: 18 · 2021: 28 · 2020: 29 · 2019: 34 · 2018: 52 · 2017: 45 · 2016: 60 · 2015: 68 · 2014: 75 · 2013: 104 · 2012: 114
- FWCI
- 51.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- INK4/ARF locus, induced pluripotent stem cells, cellular reprogramming, p16INK4a, CDKN2B, p19ARF, CDKN2A, tumor suppressor, aging, Oct4, KLF4, SOX2, large T antigen, epigenetic silencing
- MeSH terms
- Kruppel-Like Factor 4, Aging, Animals, Cell Count, Cell Differentiation, Fibroblasts, Humans, Kinetics, Mice, Inbred C57BL, Keratinocytes, Cyclin-Dependent Kinase Inhibitor p16, Gene Silencing, Pluripotent Stem Cells, Epigenesis, Genetic, Mice, Embryonic Stem Cells, Cellular Reprogramming
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