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.
Highlights
The nucleoporin Nup98 is a mobile component of the nuclear pore complex (NPC) (Griffis et al, 2002; Rabut et al, 2004; Oka et al, 2010), a sole gateway for selective nucleocytoplasmic macromolecular traffic
Our findings reveal that Nup98-HoxA9 is selectively recruited to Hox cluster regions via its interaction with Crm1 to induce gene expression in embryonic stem (ES) cells
Activation of several Hox genes by Nup98-HoxA9 has been previously reported in other types of cells (Calvo et al, 2002; Takeda et al, 2006; Ghannam et al, 2004), those effects were relatively weak and not highly specific, which is in contrast to the pronounced changes observed in our present study
Summary
The nucleoporin Nup is a mobile component of the nuclear pore complex (NPC) (Griffis et al, 2002; Rabut et al, 2004; Oka et al, 2010), a sole gateway for selective nucleocytoplasmic macromolecular traffic. Genes are stretches of DNA that contain the instructions needed to produce the proteins and RNA molecules that the cell needs to survive. These molecules move across the membrane that surrounds the nucleus through pores made of proteins. One of these pore-forming proteins is called Nup. The proteins made from these combined genes are known as “fusion proteins”
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
