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CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis

Nature Cell Biology volume 11, pages 172–182 (2009)Cite this article

Abstract

The chromodomain helicase DNA-binding (CHD) family of enzymes is thought to regulate gene expression, but their role in the regulation of specific genes has been unclear. Here we show that CHD8 is expressed at a high level during early embryogenesis and prevents apoptosis mediated by the tumour suppressor protein p53. CHD8 was found to bind to p53 and to suppress its transactivation activity. CHD8 promoted the association of p53 and histone H1, forming a trimeric complex on chromatin that was required for inhibition of p53-dependent transactivation and apoptosis. Depletion of CHD8 or histone H1 resulted in p53 activation and apoptosis. Furthermore, Chd8−/− mice died early during embryogenesis, manifesting widespread apoptosis, whereas deletion of p53 ameliorated this developmental arrest. These observations reveal a mode of p53 regulation mediated by CHD8, which may set a threshold for induction of apoptosis during early embryogenesis by counteracting p53 function through recruitment of histone H1.

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Figure 1: Anti-apoptotic activity of CHD8.
Figure 2: CHD8 interacts with and inhibits transactivation by p53.
Figure 3: CHD8 binds to the promoters of p53 target genes.
Figure 4: CHD8 recruits histone H1 to the promoters of p53 target genes.
Figure 5: Interaction of CHD8 with p53 and histone H1 is necessary for recruitment of histone H1 to the promoters of p53 target genes.
Figure 6: Requirement for histone H1 in repression of p53-mediated transcription.
Figure 7: Deletion of p53 rescues the phenotype of CHD8-deficient mice.
Figure 8: CHD8 sets a threshold for induction of apoptosis during early embryogenesis by counteracting p53 function.

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Acknowledgements

We thank T. Kitamura for pMX-puro; J. M. Cunningham and K. Hanada for the mCAT-1 plasmid; S. Miyake for the PG13-, p21-, and p21 mutant–Luc plasmids; T. Takemori for the NF-κB Luc plasmid; F. Ishikawa and R. Funayama for the N-fusion and C-fusion plasmids; M. Kitagawa for HCT116 and SaOS2 cells; M. Sato, Y. Yamada, T. Moroishi, Y. Katayama, N. Nishimura and K. Oyamada for technical assistance; M. Kimura and A. Ohta for help with preparation of the manuscript; and T. Ushijima, K. Hayashi and members of the authors' laboratories for discussion. K.I.N. was supported by Takeda Science Foundation. Y.F. and A.I.S. were supported by NIH grant CA79057. Y.F. is a GCC Cancer Scholar supported by Georgia Cancer Coalition.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Fukuoka, Japan

    Masaaki Nishiyama, Kiyotaka Oshikawa, Yu-ichi Tsukada, Tadashi Nakagawa & Keiichi I. Nakayama

  2. CREST, Japan Science and Technology Agency (JST), Kawaguchi, 332-0012, Saitama, Japan

    Masaaki Nishiyama, Kiyotaka Oshikawa, Yu-ichi Tsukada, Tadashi Nakagawa & Keiichi I. Nakayama

  3. National Institute of Advanced Industrial Science and Technology (AIST), Biological Information Research Center (JBIRC), Kohtoh-ku, 135-0064, Tokyo, Japan

    Shun-ichiro Iemura & Tohru Natsume

  4. Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, NY, USA

    Yuhong Fan & Arthur I. Skoultchi

  5. School of Biology and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, IBB 2313, 315 Ferst Drive, Atlanta, 30332-0363, GA, USA

    Yuhong Fan

  6. Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan

    Akira Kikuchi

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  1. Masaaki Nishiyama
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Contributions

M.N. performed and planned all experiments, except some of ChIP and co-immunoprecipitation experiments, which were performed by K.O., Y.T. and T. Nakagawa; K.I.N. coordinated the study, oversaw the results and wrote the manuscript; S.I. and T. Natsume contributed to proteomic analysis; Y.F. and A.I.S. provided histone H1 triple-knockout cells and many suggestions; A.K. provided antibodies to CHD8. All authors discussed the results and commented on the manuscript.

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Correspondence to Keiichi I. Nakayama.

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Nishiyama, M., Oshikawa, K., Tsukada, Yi. et al. CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis. Nat Cell Biol 11, 172–182 (2009). https://doi.org/10.1038/ncb1831

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