Independence of Repressive Histone Marks and Chromatin Compaction during Senescent Heterochromatic Layer Formation |
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Authors: | Tamir Chandra Kristina Kirschner Jean-Yves Thuret Benjamin D Pope Tyrone Ryba Scott Newman Kashif Ahmed Shamith A Samarajiwa Rafik Salama Thomas Carroll Rory Stark Rekin's Janky Masako Narita Lixiang Xue Agustin Chicas Sabrina Nũnez Ralf Janknecht Yoko Hayashi-Takanaka Michael D Wilson Aileen Marshall Duncan T Odom M Madan Babu David P Bazett-Jones Simon Tavaré Paul A W Edwards Scott W Lowe Hiroshi Kimura David M Gilbert Masashi Narita |
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Institution: | Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK. |
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Abstract: | The expansion of repressive epigenetic marks has been implicated in heterochromatin formation during embryonic development, but the general applicability of this mechanism is unclear. Here we show that nuclear rearrangement of repressive histone marks H3K9me3 and H3K27me3 into nonoverlapping structural layers characterizes senescence-associated heterochromatic foci (SAHF) formation in human fibroblasts. However, the global landscape of these repressive marks remains unchanged upon SAHF formation, suggesting that in somatic cells, heterochromatin can be formed through the spatial repositioning of pre-existing repressively marked histones. This model is reinforced by the correlation of presenescent replication timing with both the subsequent layered structure of SAHFs and the global landscape of the repressive marks, allowing us to integrate microscopic and genomic information. Furthermore, modulation of SAHF structure does not affect the occupancy of these repressive marks, nor vice versa. These experiments reveal that high-order heterochromatin formation and epigenetic remodeling of the genome can be discrete events. |
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