A. Mazumder, J. Cooper, C. Goksal, R. Y. Brockhausen, J. M. Schauss, J. S. Khanduja, A. A. Amine, R. I. Joh, J. J. Groos, J. Kanoh, M. Motamedi, I. J. Finkelstein, B. Al-Sady, S. J. Braun
Subtelomeres are imperfect repeats adjacent to telomeres that are transcriptionally repressed by heterochromatin. Although essential for genome integrity, their repetitive nature has thwarted dissection of local heterochromatin assembly and maintenance mechanisms. By engineering Schizosaccharomyces pombe strains carrying fluorescent reporters at a single subtelomere, we uncovered distinct subdomains. These subdomains have different silencing requirements: Telomere-proximal regions rely on canonical shelterin- or RNAi-dependent nucleation pathways, whereas telomere-distal regions involve nucleosome remodelers, histone chaperones, and boundary-associated factors. Sub-domains also exhibit discrete epigenetic states emerging both at homologous loci on different chromosome arms and along the same subtelomeric sequence. We document these epigenetic states using multi-generational live imaging and targeted perturbations. These analyses show that subtelomeric subdomains display position-specific, clonally variable silencing across a spectrum from robust to fragile epigenetic states. Interestingly, structural variants, common in subtelomeric sequences across eukaryotes, dictate local epigenetic stability. These findings reveal that subtelomeres, long recognized for their sequence variability, form a dynamic mosaic of coexisting epigenetic domains. This implies a wide range of gene-repressive regulatory logic at the chromosome ends, from environmental responsiveness to silencing stability.