Transcriptional memory at the nuclear periphery

Abstract

A number of inducible yeast genes are targeted to the nuclear periphery upon transcriptional activation. However, when repressed again, the INO1 and GAL1 genes remain at the nuclear periphery for multiple generations. Retention at the nuclear periphery represents a novel type of transcriptional memory; the peripherally localized, recently repressed state of GAL1 is activated more rapidly than the nucleoplasmically localized long-term repressed state of GAL1. This rapid reactivation involves localization at the nuclear periphery, the SWI/SNF chromatin remodeling complex, the histone variant H2A.Z and the Gal1 protein itself. Here, I review what we have learned about this type of transcriptional memory in yeast, what remains to be resolved and the challenges associated with understanding such epigenetic phenomena.

Figure 1. Three distinct states of the GAL genes

Initial activation of the GAL1, GAL2, GAL7 and GAL10 genes (step 1) through the Gal3 galactose sensor, leads to relocalization to the nuclear periphery through association with the NPC and the production of the Gal1 protein. Gal1 binds the repressor Gal80 and inhibits its function. After repressing transcription (via the glucose repression system), the genes remain at the nuclear periphery in a memory state that can be rapidly reactivated. The establishment of the memory state requires chromatin changes (indicated as red nucleosomes). Eventually, transcriptional memory is lost (reset, step 5). The memory state differs from the long-term repressed state in its localization, its chromatin requirements for activation and its rate of reactivation.

Figure 2. Regulation of transcriptional memory

The states and the interconversion between them are the same as in Figure 1. Conversion between the three states is regulated by the production of a cytoplasmic regulator (the Gal1 protein in the case of the GAL genes). The cytoplasmic regulator functions upstream of the SWI/SNF chromatin remodeling complex, the H2A.Z histone variant and peripheral localization (indicated as the NPC) to promote transcriptional memory (step 3). Because we cannot order these events relative to each other currently, I represent them as parallel inputs. SWI/SNF is necessary to counteract the conversion of the active state into the long-term repressed state by the ISW1 and ISW2 complexes. The memory state can be generated directly from the long-term repressed state by expression of the cytoplasmic regulator (artificial memory; step 6). Grey box: possible role for SWI/SNF, H2A.Z and peripheral localization in the generation of artificial memory.