Nucleoporin Nup98 Associates with Trx/MLL and NSL Histone-Modifying Complexes and Regulates Hox Gene Expression

•Nup98 associates and colocalizes with the MBD-R2/NSL and Trx complexes•MBD-R2 is required for recruitment of Nup98 to chromatin at a number of genes•Nup98 regulates transcription of Trx targets, the Hox genes, in development•Nup98 overexpression exhibits a homeotic transformation phenotype

SummaryThe nuclear pore complex is a transport channel embedded in the nuclear envelope and made up of 30 different components termed nucleoporins (Nups). In addition to their classical role in transport, a subset of Nups has a conserved role in the regulation of transcription via direct binding to chromatin. The molecular details of this function remain obscure, and it is unknown how metazoan Nups are recruited to their chromatin locations or what transcription steps they regulate. Here, we demonstrate genome-wide and physical association between Nup98 and histone-modifying complexes MBR-R2/NSL and Trx/MLL. Importantly, we identify a requirement for MBD-R2 in recruitment of Nup98 to many of its genomic target sites. Consistent with its interaction with the Trx/MLL complex, Nup98 is shown to be necessary for Hox gene expression in developing fly tissues. These findings introduce roles of Nup98 in epigenetic regulation that may underlie the basis of oncogenicity of Nup98 fusions in leukemia.

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