TY - JOUR T1 - Nucleolus association of chromosomal domains is largely maintained in cellular senescence despite massive nuclear reorganisation JF - bioRxiv DO - 10.1101/054908 SP - 054908 AU - Stefan Dillinger AU - Tobias Straub AU - Attila NĂ©meth Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/05/24/054908.abstract N2 - Mammalian chromosomes are organized in structural and functional domains of 0.1-10 Mb, which are characterized by high self-association frequencies in the nuclear space and different contact probabilities with nuclear sub-compartments. They exhibit distinct chromatin modification patterns, gene expression levels and replication timing. Recently, nucleolus-associated chromosomal domains (NADs) have been discovered, yet theirprecise role in chromosome organization and dynamics are still largely unknown. Here, weuse nucleolus genomics and single-cell experiments to address these questions in human embryonic fibroblasts during replicative senescence. Genome-wide mapping reveals 1,646 NADs in proliferating cells, which cover about 38& of the human genome. They aremainly heterochromatic and correlate with late replicating loci. Using Hi-C data analysis, we show that interactionsof NADs control the organization of interphase chromosomes in the 10-50 Mbdistance range. Interestingly, only minute changes in nucleolar association are observed upon senescence. These spatial rearrangements in subdomainssmaller than 100 kb are accompanied with local transcriptional changes. Incontrast, large centromeric and pericentromeric satellite repeat clusters extensively dissociate from nucleoli in senescent cells. We use gene set enrichment analysis (GSEA) to map the epigenetic regulatory network that governs these changes. The GSEA results together with cellular chromatin analyses suggest that histone H3K9 trimethylation is a key feature in regulating the nucleolus association of chromatin. Collectively, this study reveals the role of NAD interactions in shaping interphase chromosome structureand identifies connections between the nucleolus, 3D genome structure, andcellular aging. ER -