Nuclear pore proteins regulate chromatin structure and transcriptional memory by a conserved mechanism

Abstract

Previous experience alters the rate of transcriptional induction of many genes in yeast and this phenomenon persists through several cell division cycles. This phenomenon is called epigenetic transcriptional memory. For the yeast gene INO1, transcriptional memory requires a physical interaction with the nuclear pore complex (NPC) and changes in the chromatin structure of the promoter. These changes lead to binding of a preinitiation form of RNA Polymerase II (RNAPII) to the INO1 promoter, bypassing the need to recruit RNAPII to the promoter during reactivation. In our recent study, we found that in human cells, hundreds of interferon-γ responsive genes exhibit a mechanistically similar form of transcriptional memory. Transcriptional memory requires a homologous nuclear pore protein in yeast and humans, which interacts with the promoters of genes that exhibit transcriptional memory and promotes both alteration of chromatin structure and binding of RNAPII. Whereas the interaction of yeast genes with nuclear pore proteins occurs at the NPC, the interaction of human genes with nuclear pore proteins occurs in the nucleoplasm. Thus, the interaction of nuclear pore proteins with genes plays an important and conserved role in affecting long-term epigenetic changes in transcriptional regulation.

Keywords: chromatin; epigenetics; nuclear pore complex; nuclear porins; transcriptional memory.

Figure 1. Nup-dependent transcriptional memory in yeast and humans. Left, INO1 transcriptional memory in yeast. After repression, the INO1 gene remains bound to the NPC. RNAPII clears the coding region but remains associated with the promoter in a poised, preinitiation form. Promoter nucleosomes are altered by incorporation of H2A.Z and dimethylation of H3K4 (blue nucleosome). Transcriptional memory persists at the NPC for approximately four generations. Right, IFN-γ transcriptional memory in humans. After the removal of IFN-γ, a poised preinitiation form of RNAPII remains associated with the promoter. Promoter nucleosomes are marked with H3K4me2 (blue) and bind to nucleoplasmic Nups such as Nup98. This epigenetic state is inherited for at least four generations.