Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes
Masahiro Oka,
Sonoko Mura,
Kohji Yamada,
Percival Sangel,
Saki Hirata,
Kazumitsu Maehara,
Koichi Kawakami,
Taro Tachibana,
Yasuyuki Ohkawa,
Hiroshi Kimura,
Yoshihiro Yoneda
Affiliations
Masahiro Oka
Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan; Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
Sonoko Mura
Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
Kohji Yamada
Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
Percival Sangel
Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
Saki Hirata
Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan
Kazumitsu Maehara
Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan
Koichi Kawakami
Division of Molecular and Developmental Biology, National Institute of Genetics, Shizuoka, Japan
Taro Tachibana
Department of Bioengineering, Osaka City University, Graduate School of Engineering, Osaka, Japan
Yasuyuki Ohkawa
Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan
Department of Biological Sciences, Graduate School of Bioscience and Technology, Tokyo Institute of Technology, Yokohama, Japan
Yoshihiro Yoneda
Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; National Institutes of Biomedical Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
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.
