Apart from forming a physical barrier between the nucleus and the cytoplasm, allowing selective molecular exchange through nuclear pore complexes, the nuclear envelope plays an important role in chromatin organization. In particular the nuclear lamina, which is a thin layer of microfilaments coating the inner nuclear membrane, had been implicated in the spacial organization of the eukaryotic genome. Less is known about the nature of chromatin interacting with the NPC.
In yeast, nuclear pore complexes also interact with active genes, attracting or retaining them at the nuclear periphery. In higher eukaryotes, some NPC components (nucleoporins) are also found in the nucleoplasm, with so far unknown function. We have functionally characterized nucleoporin-chromatin interactions specifically at the NPC or within the nucleoplasm in Drosophila. We analyzed genomic interactions of full-length nucleoporins Nup98, Nup50 and Nup62 and nucleoplasmic and NPC-tethered forms of Nup98. We found that nucleoporins predominantly interacted with transcriptionally active genes inside the nucleoplasm. A smaller set of non-active genes interacted with the NPC. Genes strongly interacting with nucleoplasmic Nup98 were downregulated upon Nup98 depletion and activated on nucleoplasmic Nup98 overexpression. Thus, nucleoporins stimulate gene expression away from the NPC by interacting with these genes inside the nucleoplasm.
Nuclear pore complex components and cancer
Genes that interact with and respond to nucleoplasmic pools of Nup98 or Nup50 are highly enriched in developmental genes, suggesting an important function of the nucleoplasmic pool of nucleoporins on fly development. In adition, genes that interact with and respond to nucleoplasmic Nup98 are enriched in genes that are directly linked to the cell cycle. These include for example Cyclin B, Bub1 and Mad2. Interestingly, several of the nucleporin-regulated cell cycle genes have also been implicated in human cancer. For example, overexpression of Mad2 leads to tumors in transgenic mice and the human homologues of several of the group are included in "death-from-cancer" gene signatures: high expression of this signature set of genes correlates with an unfavourable outcome in several types of cancer.
Nup98 plays a causative yet incompletely understood role in human leukemia. A large number of different chromosome translocations in mainly acute myeloid leukemia (AML) result in chimaeric proteins containing the FG repeat part of Nup98 and a wide set of proteins, including homeobox transcription factors such as HoxA9. Common to all oncogenic Nup98 fusion proteins is that their localization is inside the nucleoplasm, not at the NPC.
Future research will focus on the role of nucleoplasmic nucleoporins expressed as a consequence of leukemia-associated chromosome translocations, and whether they contribute to oncogenesis by promoting expression of cell cycle genes.
See also: Gene expression: Beyond pores. Nature Reviews