Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends

Telomere-binding proteins constituting the shelterin complex have been studied primarily for telomeric functions. However, mounting evidence shows non-telomeric binding and gene regulation by shelterin factors. This raises a key question—do telomeres impact binding of shelterin proteins at distal non-telomeric sites? Here we show that binding of the telomere-repeat-binding-factor-2 (TRF2) at promoters ~60 Mb from telomeres depends on telomere length in human cells. Promoter TRF2 occupancy was depleted in cells with elongated telomeres resulting in altered TRF2-mediated transcription of distal genes. In addition, histone modifications—activation (H3K4me1 and H3K4me3) as well as silencing marks (H3K27me3)—at distal promoters were telomere length-dependent. These demonstrate that transcription, and the epigenetic state, of telomere-distal promoters can be influenced by telomere length. Molecular links between telomeres and the extra-telomeric genome, emerging from findings here, might have important implications in telomere-related physiology, particularly ageing and cancer.
Author summary Telomeres (special DNA-protein assemblies that protect chromosome ends) affect ageing and diseases such as cancer. Although this has been recognized for many years, biological processes that connect telomeres to ageing, cancer and other cellular functions remain to be fully understood. Certain proteins, believed to be only telomere-associated, engage DNA outside telomeres. This raises an interesting question. Does telomere length influence how telomere-binding proteins associate with DNA at regions distal from telomeres. If so, how does this impact function? Motivated by these questions, in the present studies we tested if extra-telomeric binding of the well-known telomere-repeat-binding-actor-2 (TRF2) depends on telomere length. Our results show that the level of DNA-bound TRF2 at telomere-distal sites changes as telomeres shorten or elongate. Consequently, TRF2-mediated gene regulation affects many genes. Notably, histone modifications that dictate chromatin compaction and access to regulatory factors, at sites distant from telomere ends also depended on telomere length. Together, this links the state of telomeres to gene regulation and epigenetics directly in ways not previously appreciated that might impact a more complete understanding of molecular processes underlying ageing and cancer.