The functional importance of telomere clustering: Global changes in gene expression result from SIR factor dispersion

Abstract

Budding yeast telomeres and cryptic mating-type loci are enriched at the nuclear envelope, forming foci that sequester silent information regulators (SIR factors), much as heterochromatic chromocenters in higher eukaryotes sequester HP1. Here we examine the impact of such subcompartments for regulating transcription genome-wide. We show that the efficiency of subtelomeric reporter gene repression depends not only on the strength of SIR factor recruitment by cisacting elements, but also on the accumulation of SIRs in such perinuclear foci. To monitor the effects of disrupting this subnuclear compartment, we performed microarray analyses under conditions that eliminate telomere anchoring, while preserving SIR complex integrity. We found 60 genes reproducibly misregulated. Among those with increased expression, 22% were within 20 kb of a telomere, confirming that the nuclear envelope (NE) association of telomeres helps repress natural subtelomeric genes. In contrast, loci that were down-regulated were distributed over all chromosomes. Half of this ectopic repression was SIR complex dependent. We conclude that released SIR factors can promiscuously repress transcription at nontelomeric genes despite the presence of ''anti-silencing'' mechanisms. Bioinformatic analysis revealed that promoters bearing the PAC (RNA Polymerase A and C promoters) or Abf1 binding consenses are consistently downregulated by mislocalization of SIR factors. Thus, the normal telomeric sequestration of SIRs both favors subtelomeric repression and prevents promiscuous effects at a distinct subset of promoters. This demonstrates that patterns of gene expression can be regulated by changing the spatial distribution of repetitive DNA sequences that bind repressive factors.

Ribosomal DNA contributes to global chromatin regulation

“…is not yet clear-inactive cistrons may bind to repressive factors (e.g., com- ponents of chromatin remodeling complexes) and deplete them from the rest of the genome, may generate a diffusible activating signal, may alter a balance between RNA polymerase I and RNA polymerase II transcripts, or a balance with other compartments or sequences (48)(49)(50)(51). Others have noted the opposite effectincreased silencing with decreased X-linked rDNA arrays of males (27,28).…”

Elimination of shelterin components bypasses RNAi for pericentric heterochromatin assembly

“…Conversely, cells containing the minichromosome Ch10 (Niwa et al 1989), which is mainly composed of pericentric repeats and centromere and telomere sequences, show reduced levels of Swi6 selectively at subtelomeric regions (Chikashige et al 2007). It is worth noting that the budding yeast, which uses Sir2/3/4 proteins to assemble heterochromatin instead of the H3K9me-HP1 system, also uses telomeres to limit silencing factors, and releasing these factors from telomeres similarly increases silencing at internal sites (Maillet et al 1996;Marcand et al 1996;Taddei et al 2009). Thus, the sequestration of silencing factors through constitutive heterochromatin domains might be especially important for genomes that are highly active to prevent ectopic heterochromatin assembly in order to maintain the epigenetic landscape.…”

Nuclear organization in genome stability: SUMO connections

“…The physiological relevance of this organization was tested in yeast by ablating the factors that sequester SIR proteins and telomeric repeats at the nuclear periphery [9]. This led to the derepression of subtelomeric genes and the promiscuous silencing of other loci at dispersed sites of the genome [9].…”

“…It is proposed that in both yeast and man, perinuclear zones contribute to gene repression by recruiting chromatin modifiers, such as the yeast Silent information regulator (SIR) complex or, in mammals, other NADindependent histone deacetylases [5][6][7][8]. The physiological relevance of this organization was tested in yeast by ablating the factors that sequester SIR proteins and telomeric repeats at the nuclear periphery [9]. This led to the derepression of subtelomeric genes and the promiscuous silencing of other loci at dispersed sites of the genome [9].…”