H2A.Z-Mediated Localization of Genes at the Nuclear Periphery Confers Epigenetic Memory of Previous Transcriptional State

Abstract

Many genes are recruited to the nuclear periphery upon transcriptional activation. The mechanism and functional significance of this recruitment is unclear. We find that recruitment of the yeast INO1 and GAL1 genes to the nuclear periphery is rapid and independent of transcription. Surprisingly, these genes remain at the periphery for generations after they are repressed. Localization at the nuclear periphery serves as a form of memory of recent transcriptional activation, promoting reactivation. Previously expressed GAL1 at the nuclear periphery is activated much more rapidly than long-term repressed GAL1 in the nucleoplasm, even after six generations of repression. Localization of INO1 at the nuclear periphery is necessary and sufficient to promote more rapid activation. This form of transcriptional memory is chromatin based; the histone variant H2A.Z is incorporated into nucleosomes within the recently repressed INO1 promoter and is specifically required for rapid reactivation of both INO1 and GAL1. Furthermore, H2A.Z is required to retain INO1 at the nuclear periphery after repression. Therefore, H2A.Z-mediated localization of recently repressed genes at the nuclear periphery represents an epigenetic state that confers memory of transcriptional activation and promotes reactivation. Eukaryotic cells control the spatial arrangement of chromosomes; the localization of genes can both reflect and contribute to their transcriptional state. A number of genes in the simple eukaryote brewer's yeast are “recruited” to the nuclear periphery through interactions with the nuclear pore complex when they are expressed. The functional significance of peripheral recruitment is unclear. Here, we show that recruited genes are actively retained at the periphery for generations after transcription is repressed. This suggests that localization at the nuclear periphery represents a novel inherited state that might allow simple eukaryotic organisms to “remember” previous transcriptional activation. This type of memory allows for more robust reactivation of genes, suggesting that it is adaptive. Finally, both retention at the nuclear periphery and rapid reactivation require a variant form of histone H2A. Adaptive memory is distinct from other types of transcriptional memory. In developmental memory, transcriptional states established by transcriptional regulators early in embryogenesis are propagated long after these regulators have disappeared. Adaptive memory does not propagate a state, but represents a novel state that serves as a source of information. In this way, it resembles a rudimentary form of cellular learning that allows cells to benefit from recent experience.