Shelterin and subtelomeric DNA sequences control nucleosome maintenance and genome stability

Abstract

Telomeres and the shelterin complex cap and protect the ends of chromosomes. Telomeres are flanked by the subtelomeric sequences that have also been implicated in telomere regulation, although their role is not well defined. Here, we show that, in Schizosaccharomyces pombe, the telomere‐associated sequences (TAS) present on most subtelomeres are hyper‐recombinogenic, have metastable nucleosomes, and unusual low levels of H3K9 methylation. Ccq1, a subunit of shelterin, protects TAS from nucleosome loss by recruiting the heterochromatic repressor complexes CLRC and SHREC, thereby linking nucleosome stability to gene silencing. Nucleosome instability at TAS is independent of telomeric repeats and can be transmitted to an intrachromosomal locus containing an ectopic TAS fragment, indicating that this is an intrinsic property of the underlying DNA sequence. When telomerase recruitment is compromised in cells lacking Ccq1, DNA sequences present in the TAS promote recombination between chromosomal ends, independent of nucleosome abundance, implying an active function of these sequences in telomere maintenance. We propose that Ccq1 and fragile subtelomeres co‐evolved to regulate telomere plasticity by controlling nucleosome occupancy and genome stability.

Telomeres and Telomere Length: A General Overview

“…The segmental duplicated region of subtelomeres contains protein coding genes that vary in copy number and is located on different chromosomes, such as WASH at 9p, 2p, Xq/Yq, 1p, 15q, and 16p; immunoglobulin heavy chain genes at 14q; and olfactory receptor genes at 1p, 6p, 8p, 11p, 15q, 19p, and 3q [82]. The subtelomeres function in the process of chromosome recognition and pairing during meiosis and are also involved in maintaining chromosomal stability and regulation of gene expression [83][84][85]. The subtelomeric homologous sequences prevent heterochromatin spreading into neighboring gene-rich regions to prevent suppression of the genes within those segments [84].…”

Subtelomeres as Specialized Chromatin Domains

“…[ 19 ] In fission yeast, DNA sequences present in TAS are intrinsically recombinogenic and promote recombination between chromosomal ends when telomerase recruitment is defective. [ 20 ]…”

“…Immediately adjacent to most telomeres, the first 10 kb include TAS that are intrinsically refractory to nucleosome formation, show low nucleosome occupancy and low levels of H3K9me2. [ 20 ] Neighboring the TAS, canonical heterochromatin spans over 50–80 kb while the adjacent telomere‐distal subtelomeric chromatin or ST chromatin shows different regional properties than bulk eu‐ or heterochromatin over ≈50 kb. [ 45 ] ST chromatin is devoid of the histone H2A variant H2AZ, shows lower levels of histone methylation [ 43,45 ] and has higher H3 occupancy than the bulk of the genome.…”

The euchromatic histone mark H3K36me3 preserves heterochromatin through sequestration of an acetyltransferase complex in fission yeast

“…Transcription of the non-coding RNA TERRA (telomeric repeat-containing non-coding RNA) from the TAS is repressed by heterochromatin and members of shelterin, the telomere-end protecting complex (Bah et al, 2012;Greenwood & Cooper, 2012). However, this subtelomeric region displays low nucleosome abundance and establishes only little H3K9me (van Emden et al, 2019). Similarly, subtelomeric 'knob' genes are decorated with a low amount of H3K9me2, and H3K36me3 is also reduced compared to euchromatin ( Figure 3C-D).…”