title: Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes.
abstract: 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.
authors.affiliation: 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.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Oka
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Mura
authors.affiliation: Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
authors.forename: Percival
authors.initials: P
authors.lastname: Sangel
authors.affiliation: Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Hirata
authors.affiliation: Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan.
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Maehara
authors.affiliation: Division of Molecular and Developmental Biology, National Institute of Genetics, Shizuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Department of Bioengineering, Osaka City University, Graduate School of Engineering, Osaka, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Tachibana
authors.affiliation: Department of Advanced Medical Initiatives, Kyushu University, Fukuoka, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohkawa
authors.affiliation: Department of Biological Sciences, Graduate School of Bioscience and Technology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Hiroshi
authors.identifier: http://orcid.org/0000-0003-0854-083X
authors.initials: H
authors.lastname: Kimura
authors.affiliation: 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.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoneda
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000378:metabolism*; D051379:Mice; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D028884:Karyopherins; D028861:Nuclear Pore Complex Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C465451:Nup98 protein, human; C097899:homeobox protein HOXA9
keywords: Chromatin; Crm1; Hox; Leukemia; Nucleoporin; Nup98; cell biology; chromosomes; genes; human; mouse