Lamina–associated chromatin in the context of the mammalian genome folding
Eukaryotic interphase chromatin is folded hierarchically. Mammalian chromosomes are partitioned into topo-logically associating domains (TADs) whose interactions with each other drive the spatial segregation of the bulk chromatin into A–compartment containing active genomic regions, and B–compartmen...
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irk-123456789-1528462019-06-14T01:27:30Z Lamina–associated chromatin in the context of the mammalian genome folding Ulianov, S.V. Shevelyov, Y.Y. Razin, S.V. Reviews Eukaryotic interphase chromatin is folded hierarchically. Mammalian chromosomes are partitioned into topo-logically associating domains (TADs) whose interactions with each other drive the spatial segregation of the bulk chromatin into A–compartment containing active genomic regions, and B–compartment harboring re-pressed genomic loci and gene deserts. The internal structure of TADs is represented by CTCF/cohesin–mediated loops. The specific local and large–scale spatial structure of chromosomes plays an important role in the regulation of the genome functions. The recruiting of the genome loci to internal nuclear structures drives a subset of long–range chromatin interactions. The nuclear lamina is found to be involved into chromatin spatial positioning within the nucleus. The chromatin–nuclear lamina interactions are not rigid allowing for a substantial reconfiguration of the genome topology in cell generations and during differentiation. Here, we review some resent findings shedding light on the nature and spatial dynamics of the lamina–associated genomic regions. Інтерфазна хроматин еукаріот характеризується ієрархічної просторовою структурою. Хромосоми ссавців розділені на топологічно асоційовані домени (тади), взаємодії яких один з одним визначають наявність хроматінових компартментов двох типів, один з яких (А-компартмент) містить активні ділянки геному, а другий - репресовані райони і генні пустелі (В-компартмент). Внутрішня структура ТАДов представлена головним чином хроматиновими петлями між ділянками зв'язування білка CTCF і когезіна. Специфічна побутовій та іншій великомасштабна просторова організація хроматину грає важливу роль в регуляції роботи генома. Частина дистанційних взаємодій в хроматині визначається залученням різних районів геному до внутрішніх структур ядра. Ядерна ламина бере участь у встановленні та підтримці просторової структури хроматину. Взаємодії хроматину з ядерної Ламін є значною мірою динамічними, що обумовлює можливість перебудови тривимірної архітектури хроматину в ряді клітинних поколінь і в процесі диференціювання. У даній оглядовій статті ми сфокусували увагу на ряді недавно отриманих експериментальних даних, що стосуються природи і динаміки взаємодій хроматину з ядерної Ламін. Интерфазный хроматин эукариот характеризуется иерархической пространственной структурой. Хромосомы млекопитающих разделены на топологически ассоциированные домены (ТАДы), взаимодействия которых друг с другом определяют наличие хроматиновых компартментов двух типов, один их которых (А–компартмент) содержит активные участки генома, а второй – репрессированные районы и генные пустыни (В–компартмент). Внутренняя структура ТАДов представлена главным образом хроматиновыми петлями между участками связывания белка CTCF и когезина. Специфическая локальная и крупномасштабная пространственная организация хроматина играет важную роль в регуляции работы генома. Часть дистанционных взаимодействий в хроматине определяется привлечением разных районов генома к внутренним структурам ядра. Ядерная ламина участвует в установлении и поддержании пространственной структуры хроматина. Взаимодействия хроматина с ядерной ламиной являются в значительной мере динамичными, что обуславливает возможность перестройки трёхмерной архитектуры хроматина в ряду клеточных поколений и в процессе дифференцировки. В данной обзорной статье мы сфокусировали внимание на ряде недавно полученных экспериментальных данных, касающихся природы и динамики взаимодействий хроматина с ядерной ламиной. 2016 Article Lamina–associated chromatin in the context of the mammalian genome folding / S.V. Ulianov, Y.Y. Shevelyov, S.V. Razin // Вiopolymers and Cell. — 2016. — Т. 32, № 5. — С. 327-333. — Бібліогр.: 41 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00092E http://dspace.nbuv.gov.ua/handle/123456789/152846 577 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
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Reviews Reviews Ulianov, S.V. Shevelyov, Y.Y. Razin, S.V. Lamina–associated chromatin in the context of the mammalian genome folding Вiopolymers and Cell |
| description |
Eukaryotic interphase chromatin is folded hierarchically. Mammalian chromosomes are partitioned into topo-logically associating domains (TADs) whose interactions with each other drive the spatial segregation of the bulk chromatin into A–compartment containing active genomic regions, and B–compartment harboring re-pressed genomic loci and gene deserts. The internal structure of TADs is represented by CTCF/cohesin–mediated loops. The specific local and large–scale spatial structure of chromosomes plays an important role in the regulation of the genome functions. The recruiting of the genome loci to internal nuclear structures drives a subset of long–range chromatin interactions. The nuclear lamina is found to be involved into chromatin spatial positioning within the nucleus. The chromatin–nuclear lamina interactions are not rigid allowing for a substantial reconfiguration of the genome topology in cell generations and during differentiation. Here, we review some resent findings shedding light on the nature and spatial dynamics of the lamina–associated genomic regions. |
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Article |
| author |
Ulianov, S.V. Shevelyov, Y.Y. Razin, S.V. |
| author_facet |
Ulianov, S.V. Shevelyov, Y.Y. Razin, S.V. |
| author_sort |
Ulianov, S.V. |
| title |
Lamina–associated chromatin in the context of the mammalian genome folding |
| title_short |
Lamina–associated chromatin in the context of the mammalian genome folding |
| title_full |
Lamina–associated chromatin in the context of the mammalian genome folding |
| title_fullStr |
Lamina–associated chromatin in the context of the mammalian genome folding |
| title_full_unstemmed |
Lamina–associated chromatin in the context of the mammalian genome folding |
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lamina–associated chromatin in the context of the mammalian genome folding |
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Інститут молекулярної біології і генетики НАН України |
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2016 |
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Reviews |
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http://dspace.nbuv.gov.ua/handle/123456789/152846 |
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Lamina–associated chromatin in the context of the mammalian genome folding / S.V. Ulianov, Y.Y. Shevelyov, S.V. Razin // Вiopolymers and Cell. — 2016. — Т. 32, № 5. — С. 327-333. — Бібліогр.: 41 назв. — англ. |
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Вiopolymers and Cell |
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327
S. V. Ulianov, Y. Y. Shevelyov, S. V. Razin
© 2016 S. V. Ulianov et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Biopolymers and Cell.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited
UDC 577
Lamina–associated chromatin in the context of the mammalian genome
folding
S. V. Ulianov1,2, Y. Y. Shevelyov3, S. V. Razin1,2
1 Institute of Gene Biology, Russian Academy of Sciences
34/5, Vavilova Str., Moscow, Russian Federation, 119334
2 Faculty of Biology, M. V. Lomonosov Moscow State University
Leninskie Gory, Moscow, Russian Federation, 119991
3 Institute of Molecular Genetics RAS,
2, Kurchatova sq., Moscow, Russian Federation, 123182
sergey.v.razin@usa.net
Eukaryotic interphase chromatin is folded hierarchically. Mammalian chromosomes are partitioned into topo
logically associating domains (TADs) whose interactions with each other drive the spatial segregation of the
bulk chromatin into A–compartment containing active genomic regions, and B–compartment harboring re
pressed genomic loci and gene deserts. The internal structure of TADs is represented by CTCF/cohesin–medi
ated loops. The specific local and large–scale spatial structure of chromosomes plays an important role in the
regulation of the genome functions. The recruiting of the genome loci to internal nuclear structures drives a
subset of long–range chromatin interactions. The nuclear lamina is found to be involved into chromatin spatial
positioning within the nucleus. The chromatin–nuclear lamina interactions are not rigid allowing for a substan
tial reconfiguration of the genome topology in cell generations and during differentiation. Here, we review
some resent findings shedding light on the nature and spatial dynamics of the lamina–associated genomic re
gions.
K e y w o r d s: nuclear lamina, chromatin compartments, TADs, loops, CTCF
Introduction
The entire nuclear space in mammals is substantially
compartmentalized [1]. Chromosomes occupy dis
tinct territories, whose internal structure is spatially
organized at multiple levels. Local and long–range
contacts between genomic regions are driven by sto
chastic motion of chromatin fiber, specific associa
tions of functionally related gene loci, direct pro
tein–protein interactions resulting in loop formation,
and by the co–occurrence of remote chromosomal
segments within nuclear bodies and specific nuclear
structures [2]. At the whole–chromosome level,
mammalian chromatin is partitioned into predomi
nantly active and generally repressed compartments,
formed by long–range interactions of topologically
associating domains (TADs) whose formation, in
turn, appears to be driven by the looping between
CTCF/cohesin–occupied regions [3].
The nuclear lamina (NL) is the largest structure
inside the nucleus. The NL represents a fibrillary
protein layer adjacent to inner nuclear membrane
and composed of several types of lamins and lamin–
associated proteins. Components of the NL were
found to be directly bound to chromatin and chroma
tin–associated regulatory factors. In mammals, about
30–40% of the genome interact with the nuclear
lamina [4]. Constitutive lamina–associated regions
Review ISSN 1993-6842 (on-line); ISSN 0233-7657 (print)
Biopolymers and Cell. 2016. Vol. 32. N 5. P 327–333
doi: http://dx.doi.org/10.7124/bc.00092E
mailto:sergey.v.razin@usa.net
328
S. V. Ulianov, Y. Y. Shevelyov, S. V. Razin
of the genome (LADs) are typically gene–poor and
AT–rich inactive genomic regions ranged between
0.1 and 10 Mb in size and are characterized by high
level of H3K9 mono–, di– and three–methylation
along with the Polycomb–associated repressive
mark H3K27me3 [4, 5]. A large cohort of studies
performed using fluorescence in situ hybridization
and various biochemical techniques have revealed
that the nuclear periphery in a vicinity of the NL rep
resents generally inactive nuclear compartment and
accumulates gene loci undergoing transcriptional re
pression during development and differentiation [6].
A number of reports on the role of the nuclear lamina
in the genome folding were published in last few
years. Here, we briefly review several recent ad
vances in understanding the chromatin spatial orga
nization and its relationships with the chromatin re
cruiting to the nuclear lamina.
The overall scheme of the chromatin spatial
organization in mammals
Recent progress in the exploration of the animal ge
nome spatial structure achieved using various high–
throughput 3C–based techniques such as 4C, 5C,
Hi–C and capture–C [7] has revealed a complex pat
tern of local and long–distance spatial interactions
within the interphase chromatin, and the basic prin
ciples of the genome folding were disclosed [1, 8].
At the whole–genome level, the spatial clustering of
small chromosomes and large chromosomes with
each other was observed in human cells [9] (Fig. 1A).
These data corroborate classical cytological obser
vations and the results of fluorescence in situ hybrid
ization showing that chromosomes occupy distinct,
largely non–overlapped chromosome territories
within the eukaryotic cell nucleus, and that small
gene–rich chromosomes are typically located within
the central part of the nucleus whereas large chromo
somes are located at the nuclear periphery [10].
At the chromosomal level, the interphase chroma
tin in mammals is partitioned into A and B chromatin
compartments [9] (Fig. 1B). The A–compartment is
formed by pairwise long–range (up to throughout
the entire chromosome) interactions of gene–dense
highly transcribed regions enriched with a broad pat
tern of active epigenetic marks. Interacting partners
could be single TADs (see below) or arrays of TADs
having a length up to dozens of megabases. In con
trast, the B–compartment is formed by long–range
interactions of inactive parts of the genome and gene
deserts. The chromatin compartment profile is con
siderably variable among different cell types. During
differentiation of the human embryonic stem cells
(ESC) a large reconfiguration of chromatin compart
ments and an expansion of the B–compartment were
observed [11]. Genes that were upregulated upon
differentiation were preferentially transferred from
B to A compartment, whereas downregulated genes
predominantly changed the compartment from A to
B. Global reorganization of chromatin compart
ments was also observed in senescent cells [12, 13].
Hence, the chromatin compartment profile reflects
the functional state of the genome.
Increase of a Hi–C map resolution to approxi
mately 50 Kb has revealed the presence of self–in
teracting regions 100–1000 Kb in length located side
by side along the chromosome and interacting with
each other relatively weak[ly] [14, 15] (Fig. 1C).
Such regions were initially called topologically as
sociating domains (TADs), or contact domains
(CDs), and are commonly interpreted as chromatin
globules. TADs have a typical size of 100–1000 Kb
in mammals and about 50–200 Kb in Drosophila
[14, 16, 17]. Mammalian TAD boundaries are en
riched with housekeeping and tRNA genes, SINE
repetitive elements and CTCF–binding sites [14]. In
Drosophila, TADs harbor predominantly repressed
genomic regions whereas TAD boundaries and in
ter–TADs contain active genes (predominantly
housekeeping) [17, 18]. TAD boundaries in mam
mals possess prominent enhancer–blocking activity.
It has been shown that communication via chromatin
loop formation between enhancers and target pro
moters typically occurs within the same TAD [19],
and TADs colocalize with the so–called “regulatory”
domains that delimit zones of enhancer influence
[20]. Thus, in terms of function, mammalian TADs
represent the transcription regulatory units of the ge
329
Lamina–associated chromatin in the context of the mammalian genome folding
Fig. 1. A schematic representa
tion of the mammalian chroma
tin spatial organization at differ
ent levels, and corresponding
illustrative Hi–C maps. A –
Chromosomes occupy distinct
territories within cell nucleus.
Large chromosomes are typi
cally located at the nuclear pe
riphery, and small ones are de
posited within the nuclear inte
rior that is manifested in the
enrichment of Hi–C–captured
contacts within clusters of large
and small chromosomes. In the
illustrative Hi–C map, shown
on the left panel, color intensity
represents interaction frequency
between the whole chromo
somes. B – Active and repressed
chromosome regions are largely
segregated from each other
within the chromosome territo
ry forming active A– and re
pressed B–compart ment. Color
intensity on the illustrative
Hi–C represents interaction fre
quency within chromatin com
partments between extended re
gions of the chromosome. C –
At megabase– and submega
base–scale, chromatin is parti
tioned into self–interacting
topologically associating do
mains (TADs) commonly inter
preted as chromatin globules.
Color intensity on the illustra
tive Hi–C represents interaction
frequency between 50 Kb ge
nomic bins. D – Inside TADs,
CTCF–binding sites interact
with each other forming loop
domains ranged between ~20–
200 Kb in size. These loops of
ten bring enhancers and pro
moters together providing posi
tive transcription regulation.
Color intensity on the illustra
tive Hi–C represents interaction
frequency between 10 Kb ge
nomic bins.
A
B
C
D
330
S. V. Ulianov, Y. Y. Shevelyov, S. V. Razin
nome. Although TAD boundaries are critical genom
ic elements preventing abnormal enhancer–promoter
communication [21], they do not completely insu
late TADs from each other: contact frequency be
tween adjacent TADs is only about 2 fold lower than
the intra–TAD contact frequency [1].
The further increase of the Hi–C maps resolution
up to 1 Kb allowed revealing the abundant presence
of CTCF–anchored chromatin loops forming the so–
called “loop domains” with a median size of 185 Kb
located inside the megabase–sized TADs [22]
(Fig. 1D). Approximately 10000 such loops were
found in the human genome. About 30% of these
loops bring the promoters and enhancers together, and
genes associated with the loops are expressed at sig
nificantly higher level than the genes whose promot
ers are not involved into looping interactions.
Interestingly, according to different estimations, 60–
90 % of loops [22, 23] are formed between conver
gent CTCF binding sites that hints the possible mech
anism of loop formation based on CTCF protein
structural features. The recently proposed model of
DNA loop extrusion successfully explains the ob
served Hi–C data [24–26]. However, the molecular
machine that actually performs the extrusion (and
consequently provides enhancer–promoter communi
cation) is currently not found. The main candidates
are RNA–polymerase II and the condensin complex
[26, 27]. Along with loop domains, the so–called “or
dinary” domains were also observed. Despite the fact
[that] the formation of these domains could not be ex
plained directly by loop extrusion, the indirect mecha
nism could be suggested: the genomic region located
between two loop domains is spatially segregated
from them that may lead to the increased contact fre
quency inside this region as compared to its contact
frequency with the flanking loop domains. Thus,
CTCF/cohesin–anchored loops represent the basic
level of the large–scale chromatin topology in mam
mals and are directly involved into long–range tran
scriptional regulation. Interestingly, CTCF–anchored
loops are not robustly detected in the Drosophila ge
nome, and TAD boundaries in Drosophila are not
considerably enriched with CTCF binding sites [18].
It denotes that mechanisms of TAD formation may be
different in mammals and insects. Recently, we have
proposed a model implementing internucleosomal in
teractions of non–acetylated repressed chromatin
(predominantly deposited within TADs in Drosophila)
as the driving force for the TAD formation and main
tenance in Drosophila [18]. Notably, the same mecha
nism could be responsible for the compaction of the
extrusion–driven loops into globular structures in
mammalian genomes.
The role of the nuclear lamina in chromatin
spatial organization
A considerable portion of the mammalian genome
(about 30–40 %) is associated with the nuclear lam
ina [4]. The mechanical aspects of chromatin tether
ing to the NL are not fully understood, but there are
at least two models [28]: zipping structure and point
ed anchors. According to the first model, the whole
LAD is recruited to the NL that is supported by the
observation that large LADs are typically attached to
the NL via long contact runs. The second model pos
tulates the existence of a limited number of anchor
points within a LAD that cooperatively provide
LAD attachment to the NL. The main candidates on
the role of such anchors are binding sites for tran
scriptional repressors [29–31]. However, in the both
models, H3K9 and H3K27 methylation appear to be
crucial for the LAD deposition at the NL, because
the readers for these epigenetic marks are located
within or are recruited to the lamina [32].
There are several controversial reports on the role
of nuclear lamina in the maintenance of the inter
phase chromatin structure in mammals. Human fi
broblasts expressing dominant–negative form of
Lamin–A (progerin) demonstrate a considerable loss
of spatial compartmentalization of active and inac
tive genome regions as revealed by Hi–C analysis,
[an] altered pattern of H3K27me3 distribution and
substantial changes of gene expression [33].
Microscopic studies have revealed that the loss of
Lamin–B1 in mouse fibroblasts results in relocation
of a gene–poor chromosome 18 from the lamina to
the nuclear interior [34], and in a human colon can
331
Lamina–associated chromatin in the context of the mammalian genome folding
cer cell line Lamin–B1 deficiency leads to decon
densation of chromosome territories [35]. On the
other hand, it has been shown that double knock–
down of Lamin B1/B2 virtually does not affect the
LAD profile and gene expression in mouse ESC
[36]. To this end, some other proteins localized with
in inner nuclear membrane could be responsible for
the chromatin positioning at nuclear periphery. The
most likely candidates are Lamin–B receptor (LBR)
and LEM–proteins such as EMD which were found
to interact with chromatin in vivo [37–39].
LAD dynamics: lessons from single–cell
studies
Dynamic interactions between the nuclear lamina
(NL) and interphase chromatin were extensively
studied in Bas van Steensel`s laboratory. The first
clear evidence for highly dynamic nature of the NL–
chromatin contacts has been obtained using the m6A–
Tracer technology based on the expression of the fu
sion of GFP protein with the DpnI restriction enzyme
recognizing methylated adenine in GATC context
[40]. As adenine–6–methylation is a stable covalent
modification, it is inheritable in cell generations al
lowing one to track the fate of LADs throughout the
cell cycle and after cell division in a living cell ex
pressing lamin fused with bacterial Dam–methylase
(the enzyme used in DamID technology to methylate
adenine in GATC context). It has been shown that
chromatin attached to the nuclear lamina possesses
remarkably constrained mobility and generally does
not migrate to the nuclear interior during interphase.
However, LADs stochastically reshuffle after mitosis
and some of them could be found in a vicinity of nu
cleoli in daughter cells. The next breakthrough tech
nology providing the further progress in understand
ing the NL–chromatin interaction mechanisms and
dynamics is a recently developed single–cell DamID
approach [41]. The current version of this method is
suitable for studying the NL–chromatin contacts in
single cells at a resolution of 100 Kb. The results ob
tained indicate that about 15% of the genome com
posed of constitutive gene–poor LADs associates
with the NL in the majority of cells. This finding sug
gests the presence of a “scaffold” structure presum
ably involved in the overall shaping of the chromo
some spatial configuration. In contrast, about 30 % of
the genome exhibit a high cell–to–cell variability in
the interaction with the nuclear lamina. Interestingly,
distantly located loci often establish the contacts with
the nuclear lamina in a coordinated manner. Further
more, it was found that at distances up to 20 Mb the
Hi–C profile moderately correlates with the degree of
NL–chromatin contacts. It is tempting to assume that
spatial interactions of remote genomic regions with
each other may direct the coordinated recruitment of
functionally–related loci to the nuclear lamina and
thus provide coordinated gene repression.
Concluding remarks
In sum, the nuclear lamina plays a remarkable role in
the genome folding and regulation. The further un
derstanding of the mechanisms involved into chro
matin tethering to the nuclear lamina could be con
siderably improved by applying new microscopic
and biochemical techniques such as super–resolu
tion live–cell imaging and combination of single–
cell DamID technique with Hi–C analysis of chro
matin configuration in the same cell.
Acknowledgments
This study was supported by the Russian Science
Foundation (project 16–14–10081).
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Хроматин асоційований з ламінами в контексті
просторової структури генома ссавців
С. В. Ульянов, Ю. Я. Шевельов, С. В. Разін
Інтерфазна хроматин еукаріот характеризується ієрархічної
просторовою структурою. Хромосоми ссавців розділені на то
пологічно асоційовані домени (тади), взаємодії яких один з од
ним визначають наявність хроматінових компартментов двох
типів, один з яких (А-компартмент) містить активні ділянки
геному, а другий – репресовані райони і генні пустелі
(В-компартмент). Внутрішня структура ТАДов представлена
головним чином хроматиновими петлями між ділянками
зв'язування білка CTCF і когезіна. Специфічна побутовій та ін
шій великомасштабна просторова організація хроматину грає
важливу роль в регуляції роботи генома. Частина дистанцій
них взаємодій в хроматині визначається залученням різних
районів геному до внутрішніх структур ядра. Ядерна ламина
бере участь у встановленні та підтримці просторової структу
ри хроматину. Взаємодії хроматину з ядерної Ламін є значною
мірою динамічними, що обумовлює можливість перебудови
тривимірної архітектури хроматину в ряді клітинних поколінь
і в процесі диференціювання. У даній оглядовій статті ми сфо
кусували увагу на ряді недавно отриманих експериментальних
даних, що стосуються природи і динаміки взаємодій хромати
ну з ядерної Ламін.
К л юч ов і с л ов а: ядерна ламина, структури хроматину,
ТАД, петлі, CTCF.
Ламина–ассоциированный хроматин в контексте
пространсвенной структуры генома млекопитающих
С. В. Ульянов, Ю. Я. Шевелёв, С. В. Разин
Интерфазный хроматин эукариот характеризуется иерархи
ческой пространственной структурой. Хромосомы млекопи
тающих разделены на топологически ассоциированные до
мены (ТАДы), взаимодействия которых друг с другом опре
деляют наличие хроматиновых компартментов двух типов,
один их которых (А–компартмент) содержит активные участ
ки генома, а второй – репрессированные районы и генные
пустыни (В–компартмент). Внутренняя структура ТАДов
представлена главным образом хроматиновыми петлями
между участками связывания белка CTCF и когезина.
Специфическая локальная и крупномасштабная простран
ственная организация хроматина играет важную роль в регу
ляции работы генома. Часть дистанционных взаимодействий
в хроматине определяется привлечением разных районов ге
нома к внутренним структурам ядра. Ядерная ламина уча
ствует в установлении и поддержании пространственной
структуры хроматина. Взаимодействия хроматина с ядерной
ламиной являются в значительной мере динамичными, что
обуславливает возможность перестройки трёхмерной архи
тектуры хроматина в ряду клеточных поколений и в процессе
дифференцировки. В данной обзорной статье мы сфокусиро
вали внимание на ряде недавно полученных эксперименталь
ных данных, касающихся природы и динамики взаимодей
ствий хроматина с ядерной ламиной.
К л юч е в ы е с л ов а: ядерная ламина, структуры хромати
на,ТАД, петли, CTCF
Received 08.08.2016
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