Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation.
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.
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Tamir
T
Chandra
Kristina
K
Kirschner
Jean-Yves
JY
Thuret
Benjamin D
BD
Pope
Tyrone
T
Ryba
Scott
S
Newman
Kashif
K
Ahmed
Shamith A
SA
Samarajiwa
Rafik
R
Salama
Thomas
T
Carroll
Rory
R
Stark
Rekin's
R
Janky
Masako
M
Narita
Lixiang
L
Xue
Agustin
A
Chicas
Sabrina
S
Nũnez
Ralf
R
Janknecht
Yoko
Y
Hayashi-Takanaka
Michael D
MD
Wilson
Aileen
A
Marshall
Duncan T
DT
Odom
M Madan
MM
Babu
David P
DP
Bazett-Jones
Simon
S
Tavaré
Paul A W
PA
Edwards
Scott W
SW
Lowe
Hiroshi
H
Kimura
David M
DM
Gilbert
Masashi
M
Narita
D001973:Bromodeoxyuridine / Q000494:pharmacology; D016922:Cellular Senescence; D002843:Chromatin / Q000737:chemistry*; D002875:Chromosomes / Q000648:ultrastructure; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D016678:Genome; D055106:Genome-Wide Association Study; D006570:Heterochromatin / Q000737:chemistry*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047569:Laser Scanning Cytometry / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods
D002843:Chromatin; D006570:Heterochromatin; D006657:Histones; D001973:Bromodeoxyuridine