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A novel ASXL1–OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies

Leukemia volume 32, pages 1327–1337 (2018)Cite this article

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Abstract

ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this novel axis inhibited myeloid differentiation and H3K4 methylation as well as H2B glycosylation and impaired transcription of genes involved in myeloid differentiation, splicing, and ribosomal functions; this has implications for myelodysplastic syndrome (MDS) pathogenesis, as each of these processes are perturbed in the disease. This axis is responsible for tumor suppression in the myeloid compartment, as reactivation of OGT induced myeloid differentiation and reduced leukemogenecity both in vivo and in vitro. Our data also suggest that MLL5, a known HCFC1/OGT-interacting protein, is responsible for gene activation by the ASXL1–OGT axis. These data shed light on the novel roles of the ASXL1–OGT axis in H3K4 methylation and activation of transcription.

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Acknowledgements

We thank LW. Deng and X. Yu for providing plasmids. This work is supported by the Grants-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, A research grant from the Tokyo Biochemical Research Foundation, and A research grant from the Uehara Memorial Foundation.

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Authors and Affiliations

  1. Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 1088639, Japan

    Daichi Inoue, Takeshi Fujino, Reina Nagase, Sayuri Horikawa, Makoto Saika, Kimihito Cojin Kawabata, Susumu Goyama & Toshio Kitamura

  2. Laboratory of Genome Data Base, The Institute of Medical Science, The University of Tokyo, Tokyo, 1088639, Japan

    Paul Sheridan, Yao-zhong Zhang, Rui Yamaguchi, Seiya Imoto & Satoru Miyano

  3. Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Zaomin Li, Mingjiang Xu & Feng-Chun Yang

  4. Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 8608556, Japan

    Hirotaka Matsui

  5. Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 7348553, Japan

    Akinori Kanai & Toshiya Inaba

  6. Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo, 1088639, Japan

    Hiroko Kozuka-Hata & Masaaki Oyama

  7. Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan

    Akihiko Yokoyama

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  1. Daichi Inoue
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Inoue, D., Fujino, T., Sheridan, P. et al. A novel ASXL1–OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies. Leukemia 32, 1327–1337 (2018). https://doi.org/10.1038/s41375-018-0083-3

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