The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats

Abstract

The study of the proteins that bind to telomeric DNA in mammals has provided a deep understanding of the mechanisms involved in chromosome-end protection. However, very little is known on the binding of these proteins to nontelomeric DNA sequences. The TTAGGG DNA repeat proteins 1 and 2 (TRF1 and TRF2) bind to mammalian telomeres as part of the shelterin complex and are essential for maintaining chromosome end stability. In this study, we combined chromatin immunoprecipitation with high-throughput sequencing to map at high sensitivity and resolution the human chromosomal sites to which TRF1 and TRF2 bind. While most of the identified sequences correspond to telomeric regions, we showed that these two proteins also bind to extratelomeric sites. The vast majority of these extratelomeric sites contains interstitial telomeric sequences (or ITSs). However, we also identified non-ITS sites, which correspond to centromeric and pericentromeric satellite DNA. Interestingly, the TRF-binding sites are often located in the proximity of genes or within introns. We propose that TRF1 and TRF2 couple the functional state of telomeres to the long-range organization of chromosomes and gene regulation networks by binding to extratelomeric sequences.

Extra-Telomeric Roles of Telomeric Proteins

“…Given the reported role of TRF1 and TRF2 in the control of replication fork progression through telomeric chromatin (Sfeir et al 2009;Ye et al 2010), it is possible that these shelterin components play a similar role in other regions of DNA that are difficult to replicate, such as those packaged as heterochromatin. Gene ontology data (Simonet et al 2011) suggested that a large subset of TRF binding sites may have functional relevance since they occur more frequently within or in close proximity to genes, which agrees with results from Martinez et al, since TRF sites are frequently located in intronic regions or distant from promoters (Simonet et al 2011). Thus, TRF1 and TRF2 possibly regulate gene expression through looping mechanisms or by modifying the chromatin landscape.…”

“…It should be noted that this Rap1 localization to various sites was not in response to any cellular stress. However, these data are slightly divergent from two subsequent reports also analyzed binding of telomeric proteins to extra-telomeric chromosomal sites by ChIP-seq (Simonet et al 2011;Yang et al 2011). …”

“…It is possible that cellular levels of TRF proteins influence their binding to the ITSs, and thus the expression of neighboring genes. Interestingly, they also observe from sequence alignments of bound and unbound extratelomeric sites that TRF1 and TRF2 discriminate between different sites on the basis of their length and sequence (Simonet et al 2011). This observation suggests that other features such as accessibility and/or the chromatin structure of the surrounding DNA region may influence TRF binding.…”

“…A novel finding of the second study of TRF1 and TRF2 genome-wide binding by Simonet et al was the identification of non-ITS binding sites centered on (ATTCC)n satellite 2/3 repeats or alphoid DNA satellite sequences, which form part of the most prominent autosomal heterochromatin blocks (Simonet et al 2011). Given the reported role of TRF1 and TRF2 in the control of replication fork progression through telomeric chromatin (Sfeir et al 2009;Ye et al 2010), it is possible that these shelterin components play a similar role in other regions of DNA that are difficult to replicate, such as those packaged as heterochromatin.…”

Genome rearrangements caused by interstitial telomeric sequences in yeast

“…S-ITSs are believed to represent insertions of telomeric repeats that occur during the repair of double-stranded DNA breaks (5). A subset of s-ITSs in the human genome is bound by the shelterin proteins Rap1, TRF1, and TRF2 (6). In primates and rodents, s-ITSs colocalize with some of the chromosomal fragile sites (7,8) and map to chromosome breakpoints in cancer cells (9).…”