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Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes
Journal article

Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes

  • Oka, Masahiro Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
  • Mura, Sonoko Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
  • Yamada, Kohji Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
  • Sangel, Percival Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
  • Hirata, Saki Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan
  • Maehara, Kazumitsu Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan
  • Kawakami, Koichi Division of Molecular and Developmental Biology, National Institute of Genetics, Shizuoka, Japan
  • Tachibana, Taro Department of Bioengineering, Osaka City University, Graduate School of Engineering, Osaka, Japan
  • Ohkawa, Yasuyuki Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan
  • Kimura, Hiroshi ORCID Department of Biological Sciences, Graduate School of Bioscience and Technology, Tokyo Institute of Technology, Yokohama, Japan
  • Yoneda, Yoshihiro National Institutes of Biomedical Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
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  • 2016-1-7
Published in:
  • eLife. - eLife Sciences Publications, Ltd. - 2016, vol. 5
English The nucleoporin Nup98 is frequently rearranged to form leukemogenic Nup98-fusion proteins with various partners. However, their function remains largely elusive. Here, we show that Nup98-HoxA9, a fusion between Nup98 and the homeobox transcription factor HoxA9, forms nuclear aggregates that frequently associate with facultative heterochromatin. We demonstrate that stable expression of Nup98-HoxA9 in mouse embryonic stem cells selectively induces the expression of Hox cluster genes. Genome-wide binding site analysis revealed that Nup98-HoxA9 is preferentially targeted and accumulated at Hox cluster regions where the export factor Crm1 is originally prebound. In addition, leptomycin B, an inhibitor of Crm1, disassembled nuclear Nup98-HoxA9 dots, resulting in the loss of chromatin binding of Nup98-HoxA9 and Nup98-HoxA9-mediated activation of Hox genes. Collectively, our results indicate that highly selective targeting of Nup98-fusion proteins to Hox cluster regions via prebound Crm1 induces the formation of higher order chromatin structures that causes aberrant Hox gene regulation.
Language
  • English
Open access status
gold
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Persistent URL
https://sonar.ch/global/documents/189104
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