The role of nuclear pore proteins in epigenetic regulation and spatial organization of the genome (471.2)

Abstract

In yeast and metazoa, active genes interact with nuclear pore proteins, which promotes stronger transcription. Targeting to the NPC in yeast is mediated by cis‐acting “DNA zip codes” that are necessary and sufficient to confer targeting to the nuclear periphery. Loci with the same zip codes cluster together. Some inducible genes remain associated with the NPC for several generations after being repressed, a phenomenon called epigenetic transcriptional memory. This interaction poises genes for future reactivation and requires the nuclear pore protein Nup100, a homologue of human Nup98. A similar phenomenon occurs in human cells; for at least four generations after treatment with interferon gamma (IFNg), many IFNg‐inducible genes are induced more rapidly and more strongly than in cells that have not previously been exposed to IFNg. In both yeast and human cells, the recently expressed promoters of genes with memory exhibit persistent dimethylation of histone H3 lysine 4 (H3K4me2) and physically interact with Nups and a poised form of RNA polymerase II. Transcriptional memory in yeast requires several chromatin modifications: H2B ubiquitination, H3K4 methylation and the SET3C histone deacetylase. In human cells transiently depleted of Nup98 or yeast cells lacking Nup100, transcriptional memory is lost; RNA polymerase II does not remain associated with promoters, H3K4me2 is lost, and the rate of transcriptional reactivation is reduced. Thus, Nup binding to active genes plays a conserved role in promoting stronger transcription and Nup binding to recently expressed promoters plays a conserved role in promoting epigenetic transcriptional memory.