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Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription

Nature Cell Biology volume 10, pages 102–109 (2008)Cite this article

Abstract

The remarkable stability of gene expression in somatic cells is exemplified by the way memory of an active gene state is retained when an endoderm cell nucleus is transplanted to an enucleated egg1. Here we analyse the mechanism of a similar example of epigenetic memory. We find that memory can persist through 24 cell divisions in the absence of transcription and applies to the expression of the myogenic gene MyoD in non-muscle cell lineages of nuclear transplant embryos. We show that memory is not explained by the methylation of promoter DNA. However, we demonstrate that epigenetic memory correlates with the association of histone H3.3 with the MyoD promoter in embryos that display memory but not in those where memory has been lost. The association of a mutated histone H3.3 (H3.3 E4, which lacks the methylatable H3.3 lysine 4) with promoter DNA eliminates memory, indicating a requirement of H3.3 K4 for memory. We also show that overexpression of H3.3 can enhance memory in transplanted nuclei. We therefore conclude that the association of histone H3.3 with the MyoD promoter makes a necessary contribution to this example of memory. Hence, we suggest that epigenetic memory helps to stabilize gene expression in normal development; it might also help to account for the inefficient reprogramming in some transplanted nuclei.

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Figure 1: Nuclear transfer and epigenetic memory.
Figure 2: Association of HA-tagged histone H3.3 with the epigenetic memory of MyoD.
Figure 3: The E4 mutant of H3.3 suppresses epigenetic memory of MyoD.
Figure 4: H3.3 overexpression and epigenetic memory of other myogenic genes.

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Acknowledgements

We thank G. Almouzni, A. Bannister, P. Hurd and W. Reik for valuable discussion, W. Reik for use of the real-time PCR machine, G. Nigel for the construction of E4 mutants, and H. Standley for assistance. This work was funded by the Wellcome Trust and the BBSRC.

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  1. Ray Kit Ng

    Present address: Present address: Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB22 3AT, UK,

Authors and Affiliations

  1. Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, CB2 1QN, Cambridge, UK

    Ray Kit Ng & J. B. Gurdon

  2. Department of Zoology, University of Cambridge, UK

    Ray Kit Ng & J. B. Gurdon

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  1. Ray Kit Ng
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  2. J. B. Gurdon
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Correspondence to J. B. Gurdon.

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Ng, R., Gurdon, J. Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription. Nat Cell Biol 10, 102–109 (2008). https://doi.org/10.1038/ncb1674

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