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Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming

Nature Cell Biology volume 14, pages 457–466 (2012)Cite this article

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An Erratum to this article was published on 30 May 2012

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Abstract

Transcription-factor-directed reprogramming from somatic cells to induced pluripotent stem cells (iPSCs) is by nature an epigenetic process of cell fate change. Previous studies have demonstrated that this inefficient process can be facilitated by the inclusion of additional factors. To gain insight into the reprogramming mechanism, we aimed to identify epigenetic enzymes capable of promoting iPSC generation. Here we show that Kdm2b, a histone H3 Lys 36 dimethyl (H3K36me2)-specific demethylase, has the capacity to promote iPSC generation. This capacity depends on its demethylase and DNA-binding activities, but is largely independent of its role in antagonizing senescence. Kdm2b functions at the beginning of the reprogramming process and enhances activation of early responsive genes in reprogramming. Kdm2b contributes to gene activation by binding to and demethylating the gene promoters. Our studies not only identify an important epigenetic factor for iPSC generation, but also reveal the molecular mechanism underlying how Kdm2b contributes to reprogramming.

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Figure 1: Kdm2b promotes iPSC generation.
Figure 2: iPSCs generated by enforced expression of OSK plus Kdm2b are pluripotent.
Figure 3: Kdm2b facilitates iPSC generation in a JmjC- and ZF-domain-dependent manner.
Figure 4: Kdm2b promotes iPSC generation independently of Ink4a/Arf.
Figure 5: Kdm2b exerts its effect from the beginning of the reprogramming process and facilitates gene activation early in reprogramming.
Figure 6: Kdm2b activates early responsive genes in reprogramming.
Figure 7: Kdm2b localizes on and demethylates the promoter region of early-activated genes.
Figure 8: Inhibition of the expression of early-activated genes compromises the capacity of Kdm2b to enhance iPSC generation.

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  • 25 April 2012

    In the version of this Article originally published, in the legend for Fig. 4, the statement "Data in a and d represent the mean of two independent experiments" should have read: "Data in a and e represent the mean of two independent experiments". This error has been corrected in both the HTML and PDF versions of the Article.

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Acknowledgements

We thank UNC Animal Models Core for chimaera generation and UNC Functional Genomic Core for microarray analysis. We thank S. Yamaguchi and K-H. Hong for helpful discussions. This work is supported by U01DK089565 from the NIH. Y.Z. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA

    Gaoyang Liang, Jin He & Yi Zhang

  2. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA

    Gaoyang Liang, Jin He & Yi Zhang

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  1. Gaoyang Liang
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Contributions

G.L. and Y.Z. designed all of the experiments and wrote the manuscript. G.L. performed most of the experiments. J.H. constructed the Kdm2b plasmids and lentiviral doxycyclin inducible system.

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Correspondence to Yi Zhang.

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The authors declare no competing financial interests.

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Liang, G., He, J. & Zhang, Y. Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nat Cell Biol 14, 457–466 (2012). https://doi.org/10.1038/ncb2483

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