Download On form and function: does chromatin packing regulate the cell cycle?

Physiol Genomics 46: 191–194, 2014.
First published January 28, 2014; doi:10.1152/physiolgenomics.00002.2014.
Perspectives
On form and function: does chromatin packing regulate the cell cycle?
David C. Corney and Hilary A. Coller
Molecular, Cell and Developmental Biology, University of California, Los Angeles, California; and Department of Biological
Chemistry, David Geffen School of Medicine, Los Angeles, California
Submitted 9 January 2014; accepted in final form 23 January 2014
epigenetics; quiescence; histone modifications
processes that control heritable
changes in gene expression that are not due to changes in the
DNA sequence. Therefore, while the sequence of DNA bases
is a centrally important determinant of a cell’s properties, cells
can confer information to their progeny through mechanisms in
addition to the sequence of DNA bases. One example is that
the DNA and the proteins with which it interacts, the chromatin, are modified without affecting its coding potential. For
example, DNA can be modified through the addition of methyl
groups at the C5 position of cytosine within CpG dinucleotides
(20). CpG dinucleotides occur frequently at mammalian promoter regions in “CpG islands,” where hypermethylation often
results in a more compact formation of the chromatin. By
inhibiting the accessibility of chromatin to transcription factors, enhancers, and the transcriptional machinery, CpG methylation inhibits transcription initiation. Interestingly, thousands
of so-called “orphan” CpG islands, intergenic or intragenic
CpG islands distant from known promoters, have been recently
identified within the human genome and represent ⬃50% of
human CpG islands (19, 33). Although their function is largely
unknown, they have been hypothesized to function during
development (19, 33). When present near transcription start
sites, promoter DNA methylation can modulate the expression
of cell type-specific genes as cells differentiate during normal
development. Promoter hypermethylation at CpG islands can
silence tumor suppressor genes (28), while global hypomethylation is associated with deregulated expression of tumor suppressors, activity of repetitive elements such as LINE and
EPIGENETICS REFERS TO THE
Address for reprint requests and other correspondence: *Corresponding
author: H. A. Coller, Molecular, Cell and Developmental Biology, Univ. of
California, Los Angeles, Los Angeles, CA 90095 (e-mail: [email protected]).
SINE, and consequently increased genomic instability and
predisposition to tumor formation (14, 17). Thus, CpG methylation can affect gene expression, genomic instability, and
tumor susceptibility.
Modification of the DNA packaging proteins, the octamers
of histones that form nucleosomes, in addition to the DNA
itself, allows for more opportunities for the regulation of
chromatin state and can thus affect gene expression and cellular state (30, 58). The NH2-terminal tails of each histone are
exposed to the nucleoplasm where they are susceptible to
covalent modification. A wide range of posttranslational modifications have been identified, including mono-, di-, and trimethylation, acetylation, phosphorylation, ubiquitination, and
others, each of which can affect the state of chromatin depending on the histone, modified amino acid, and position within
the histone (2). Changes in chromatin state that result from
these different modifications of histones can alter DNA accessibility in order to modulate the recruitment of other histonemodifying enzymes and regulators of transcription (27). For
example, acetylation neutralizes the negative charge of lysine
residues, thereby reducing internucleosomal interaction and
promoting an open conformation that is accessible to transcription factor binding (29, 55). These characteristics of CpG
promoter methylation, and histone modifications associated
with actively transcribed genes, have proved useful in identifying novel genes, such as noncoding RNAs (54). Furthermore,
interrogation of the epigenetic modifications associated with
disease, together with transcriptional profiling experiments, has
allowed for a more complete understanding of the processes
underlying various disorders including diabetes (34), cardiomyopathy (24, 25), and colorectal cancer (54).
Epigenetics and Quiescence
Epigenetics has been shown to play a role in the commitment to proliferation or cell cycle arrest. The members of the
retinoblastoma family act as a brake on the cell cycle, opposing
cell cycle progression promoted by the E2F1–3 transcription
factors. Retinoblastoma proteins repress transcription of cell
cycle-promoting genes by recruiting the corepressor Sin3B,
which in turn recruits the histone deacetylases 1 and 2 to the
promoters of E2F target genes (8, 16, 43). The histone deacetylases remove acetyl groups from histone lysines and make the
chromatin in the promoters of E2F genes more compact, thus
repressing transcriptional activation. Cells derived from mSin3bdeficient mice cycle normally under proliferative conditions but
are unable to exit the cell cycle in response to limiting growth
factors (8). As another example, mixed lineage leukemia 5
(MLL5) is induced as myoblasts enter quiescence (49). MLL5
mediates cell cycle arrest by increasing methylation of H3K4
in the promoter of the cyclin A gene, thus reducing cyclin A
expression (49). Cell cycle arrest in response to DNA damage
can also be mediated through epigenetic changes. After an
1094-8341/14 Copyright © 2014 the American Physiological Society
191
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Corney DC, Coller HA. On form and function: does chromatin packing
regulate the cell cycle? Physiol Genomics 46: 191–194, 2014. First published
January 28, 2014; doi:10.1152/physiolgenomics.00002.2014.—The Systems Biology of Cell State Regulation Section is dedicated to considering how we can define a cellular state and how cells transition
between states. One important decision that a cell makes is whether to
cycle, that is, replicate DNA and generate daughter cells, or to exit the
cell cycle in a reversible manner. The members of the Systems
Biology of Cell State Regulation Editorial Board have an interest in
the role of epigenetics and the commitment to a dividing or nondividing state. The ability of cells to transition between proliferating and
nonproliferating states is essential for the proper formation of tissues.
The ability to enter the cell cycle when needed is necessary for
complex multicellular processes, such as healing injuries or mounting
an immune response. Cells that fail to quiesce properly can contribute
to the formation of tumors. In this perspective piece, we focus on
research exploring the relationship between epigenetics and the cell
cycle.
Perspectives
192
EPIGENETICS AND QUIESCENCE
event that damages DNA, the ING2 protein recognizes and
binds H3K4me3 marks in the cyclin D2 promoter (40, 50),
recruits the Sin3a-histone deacetylase 1 complex and silences
cyclin D1 expression (50). Thus, in response to quiescence
signals or damaged DNA, epigenetic changes have been discovered to be important intermediates in signaling pathways
that control proliferation.
Histone H4K20
Knockdown of Suv4-20h2 Results in Loss of Compaction and
Quiescence Entry
To further explore the importance of H4K20 in quiescence,
we monitored the amount of compaction in cells with knockdown of Suv4-20h1 or Suv4-20h2 using siRNA pools that
achieved an ⬃60% reduction in the levels of the targeted
transcripts. The siRNA pool against Suv4-20h1 increased the
distance between the foci but did not achieve statistical significance, whereas treatment with an siRNA pool against Suv420h2 resulted in a statistically significant increase in chromosome size (10). We determined the effect of the knockdowns on
proliferation and quiescence and discovered that the percentage of
actively cycling cells was significantly higher for fibroblasts
transfected with siRNAs directed against Suv4-20h2, but not
Suv4-20h1, compared with a control set of siRNAs (10). After
contact inhibition, cell populations in which Suv4-20h2 was
depleted also contained a greater fraction of cycling cells than
controls (10). While the fibroblasts initially exhibit a higher
fraction of cells in S phase, when they were followed over time,
cell number declined, which may reflect genomic instability
associated with proliferation under conditions of inappropriate
chromatin conformation. These findings indicate that not only do
the levels of the higher methylated forms of H4K20 increase with
quiescence, but that the methylation state of H4K20 may play a
functional role in both chromatin compaction and the control of
cell cycle progression.
H4K20 is Induced in Quiescence
Using a model of quiescence in primary human dermal
fibroblasts, we monitored the extent of chromatin compaction
using dual-color fluorescence in situ hybridization with probes
for two loci on chromosome 16 to monitor the extent of
chromatin compaction in collaboration with the Dyson lab
(Massachusetts General Hospital). Contact-inhibited fibroblasts exhibited a smaller interprobe distance than proliferating
or restimulated cells (10). Thus, in primary human fibroblasts,
entry into quiescence in response to contact inhibition resulted
in more tightly packed chromatin that was reversibly unpacked
upon cell cycle reentry. To quantitatively measure the changes
in global histone modifications between proliferating and contact-inhibited fibroblasts, histones were analyzed by liquid
chromatography-mass spectrometry in collaboration with Prof.
Ben Garcia (University of Pennsylvania). Mass spectrometry
allowed for a highly quantitative analysis of ⬃50 histone
modifications in a single experiment. Surprisingly, after 14 or
21 days of contact inhibition, most histone modifications were
Fig. 1. Models of the role of Suv4-20h2 in quiescence. Following entry into
quiescence, levels of trimethylated H4K20 (H4K20me3) are elevated. Suv420h2 contains a SET domain that is responsible for H4K20 methyltransferase
activity (red lines), as well as a COOH-terminal clamp domain that has been
reported to regulate chromatin compaction in mouse embryonic fibroblasts
(blue line). In primary human fibroblasts, Suv4-20h2 knockdown results in
increased proliferation and reduced chromatin compaction. Further research
will be required to determine whether H4K20me3 is directly involved in the
compaction or proliferation phenotypes. Chromatin compaction and proliferation may reflect 2 independent Suv4-20h2 functions (dashed line), or chromatin compaction may regulate proliferation state either directly or via gene
expression changes (dashed lines).
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Among the histone modifications that play a functional role
in chromatin activity, our data led us to focus on lysine 20 of
histone H4 (H4K20). Levels of singly methylated H4K20 are
cell cycle dependent (1, 7, 21, 39, 41, 57), and methylation of
H4K20 has been implicated in cell cycle progression, chromosome condensation, transcription, and licensing of origins of
replication (6, 18, 23, 39, 44, 51, 53). PR-Set-7, an enzyme that
generates monomethylated H4K20, H4K20me (12, 38), is
actively targeted for proteasome-mediated degradation in S
phase (1, 21, 22, 44, 53, 57) and exhibits high activity during
mitosis (57). Dimethylated H4K20, H4K20me2, serves as a
binding site for the DNA damage recognition protein 53BP1
and thereby facilitates repair of double strand breaks (5, 45).
H4K20me3 has been implicated in heterochromatin maintenance
and is found at telomeres (3, 26, 31, 47) and repeated elements
including transposable elements (32, 35, 36). Deletion of Suv420h2 leads to longer telomeres (3) and induces the expression of
transposons in Drosophila (42). In humans and mice, H4K20me2
and H4K20me3 levels are regulated by a pair of closely related
paralogs, Suv4-20h1 and Suv4-20h2. Deletion of Suv4-20h1 results in depletion of H4K20me2, while deletion of Suv4-20h2
results in depletion of H4K20me3 (48).
Loss of H4K20me3 is a common hallmark of human cancer
(13, 46, 56). In a large panel of different types of cancer cells
and in pairs of tumors and matched normal tissue, H4K20me3
levels were consistently low in cancer cells (13). In lung and
bladder cancer, H4K20me3 levels decreased with increasing
tumor grade, and H4K20me3 levels predicted survival (46, 56).
Teratomas generated from induced pluripotent stem cells doubly deficient for Suv4-20h1 and Suv4-20h2 exhibit an enhanced growth rate compared with wild-type controls (31).
present at similar levels in proliferating and quiescent fibroblasts (10, 11). Out of the 48 modification states monitored, 44
exhibited less than a twofold change. The modification with the
largest change in abundance among the states was H4K20,
with an approximately eightfold induction in H4K20me3. Restimulation of quiescent cells resulted in a reduction in
H4K20me3 levels. Our findings demonstrate that changes in
the pattern of H4K20 methylation occur consistently in cells
that have exited the proliferative cell cycle and that the changes
are reversible in quiescent fibroblasts.
Perspectives
EPIGENETICS AND QUIESCENCE
Suv4-20h2 Itself Interacts With Chromatin
Outstanding Questions for the Field
Taken together, our findings leave open several important
questions. What is the functional role of the chromatin compaction that occurs during quiescence and what are its key
mediators? More specifically, does Suv4-20h2 mediate the
changes in chromatin compaction with quiescence, and are
these effects a result of change in H4K20 methylation or do
they reflect the direct interaction of Suv4-20h2 with heterochromatin (Fig. 1)? Are the changes in proliferation as a result
of Suv4-20h2 knockdown a consequence of the changes in
chromatin compaction? If so, is this effect mediated through
changes in the expression of specific genes? And finally, do the
chromatin compaction changes mediated by Suv4-20h2 affect
a cell’s propensity for tumorigenesis?
If changes in chromatin are sufficient to make cells more or
less proliferative, then changes in the activity of these molecules, or changes in chromatin state, may be an important
regulator of the transitions between proliferation and cell cycle
arrest. Inappropriate proliferation, or a failure to proliferate
when needed, may contribute to developmental disorders and
to pathologies including cancer (4, 9, 52). Histone modifications are being intensively investigated as tumor markers and
as targets for therapy (37). A better understanding of the
relationship between quiescence and epigenetics may provide
important information about the approaches most likely to
succeed in cancer therapies targeted to histone modifications.
GRANTS
H. A. Coller is supported by National Institute of General Medical Sciences
(NIGMS) Center of Excellence Grant P50 GM-071508, the Cancer Institute of
New Jersey, the New Jersey Commission on Cancer Research, National
Cancer Institute 1RC1 CA147961-01, a Focused Funding Grant from the
Johnson & Johnson Foundation, NIH/NIGMS 1R01 GM-081686, NIH/
NIGMS 1R01 GM-086465, Jonsson Comprehensive Cancer Center, and a
Leukemia/Lymphoma Society New Idea Award. H. A. Coller was a Milton E.
Cassel scholar of the Rita Allen Foundation. D. C. Corney acknowledges
National Institute of Diabetes and Digestive and Kidney Diseases Grant
U01DK-085527.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: D.C.C. and H.A.C. drafted manuscript; D.C.C. and
H.A.C. edited and revised manuscript; D.C.C. and H.A.C. approved final
version of manuscript.
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