Nucleoporins Directly Stimulate Expression of Developmental and Cell-Cycle Genes Inside the Nucleoplasm

Abstract

Nuclear pore complexes (NPCs) mediate transport across the nuclear envelope. In yeast, they 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 a 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, in particular those involved in developmental regulation and the cell cycle. A smaller set of nonactive 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 developmental and cell-cycle gene expression away from the NPC by interacting with these genes inside the nucleoplasm.

Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila

“…Studies have shown that Nup98 localizes predominantly to the nuclear pore complex, but has an additional population in the nucleoplasm and can exhibit altered nuclear distribution in response to some stimuli, such as developmental signaling or IFN-γ (19,20,22,34). In our system, we found that Nup98 levels are increased on viral infection (Fig.…”

“…The classically described role for Nups is within the nuclear pore complex, with specific functions in the transport of macromolecules in and out of the nucleus (37-39); however, recent studies have found both on-pore and off-pore roles for a subset of Nups (19,20). Using two independent assays, we found no defect in nuclear export or import on depletion of Nup98 or several other nuclear pore proteins.…”

“…Recent studies have revealed a direct role for Nup98 in gene expression, particularly in the transcriptional regulation of developmental and immune genes (19,20,22,35). Thus, we hypothesized that Nup98 may similarly regulate the expression of antiviral genes independent of its role in nucleo-cytoplasmic transport.…”

“…Nup98-dependent control of gene expression has been linked to its occupancy at target promoters (19,20). Indeed, we chose B52 because Nup98 was found at the B52 promoter in ChIP-chip studies performed in Drosophila S2 cells (19).…”

“…The intranuclear accumulation of one such Nup, Nup98, is linked to ongoing nuclear transcription and chemical inhibition of RNA polymerase II was shown to abrogate its intranuclear mobility (17,18). Moreover, Nup98 was subsequently found to directly control gene expression of a subset of developmentally regulated genes (19)(20)(21). Nup98 is recruited to these loci during developmental transcriptional activation, and this association is required for the expression of such genes, particularly for the rapid induction of hormoneactivated developmental gene targets (19).…”