Journal
MOLECULAR CELL
Volume 47, Issue 2, Pages 203-214Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2012.06.010
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Funding
- Cambridge NIHR Biomedical Research Centre
- University of Cambridge
- Cancer Research UK
- Hutchison Whampoa
- UK Medical Research Council
- Human Frontier Science Program
- JST CREST
- MEXT of Japan
- Canadian Institutes of Health Research
- National Institute of General Medicine [GM083337, GM085354]
- Cancer Research UK [15890, 19556, 15603, 14545] Funding Source: researchfish
- Medical Research Council [MC_U105185859] Funding Source: researchfish
- MRC [MC_U105185859] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [22370063] Funding Source: KAKEN
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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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