Chromatin Looping and Organization at Developmentally Regulated Gene Loci - Daan Noordermeer - Academia

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6/24/2014 Chromatin looping and organization at developmentally regulated gene loci | Daan Noordermeer - Academia.edu

WIREs Developmental Biology Chromatin looping and organization during development
cells. In nonrecombined pre-pro-B cells and in pro-
B cells that are recombination decient, a (pre-)
structure is detected that brings VH (variable), DH
(diversity), and JH(joining)regionstogether.
43
Triple
color FISH experiments were used to determine the
3D organization in single cells, although the use of
uorescent probes restricted the number of viewpoints
thatcouldbeaddressedwithinthelocus.Modelingof
these interactions in the twodevelopmentally different
cell types showed that the Igh locus becomes more
compacted prior to recombination. However, within
this 3D structure, the different regions obtain more
freedomtointeractwitheachother.Assuch,the3D
organization of this prestructure may prepare theIgh
locus for maximum diversity of interactions during
thelaterrecombinationstage.
Silent and Alternative Loops: Distraction or
Repression?
While many examples of chromatin loops involving
enhancers and insulators are known, denitive
evidence for chromatin loops, which would directly
silence genes is, to our knowledge, lacking.
Interestingly, at two Drosophila loci, the Snail
repressor actively inhibits the formation of active
loops,amechanismcoinedanti-looping.
44
Similarly,
silent chromatin loops at mammalian loci may act by
distracting genes from forming active loops, which
may lead to the same regulatory outcome as anti-
looping. One example of potential distracting loops
acetylated marked regions, which may potentially
haveenhanceractivities.Deletionstudies,combined
with 3C experiments should provide a distinction
betweenthesehypotheses.
Inmouseerythroidcells,theKitlocusprovidesa
similar example of alternative active andsilent loops
46
(Figure3(e)). The active Kitlocus is bound at two sites
byGATA-2,whenGATA-1isabsent,asdetermined
in a GATA-1 inducible cell line (see Building a -
globinACHandRef29).WhenboundbyGATA-2,
anupstreamenhancer(114kb)formsachromatin
loop with a site located 5 kb downstream (+5kb)
fromthe Kit transcriptional start site
46
(Figure3(e)).
WhenGATA-1is present inthenucleus, theGata2 and
Kitgenesarerepressed.InsteadofGATA-2,GATA-1
now binds both the 114kband +5kbsites,while
additionalGATA-1bindingisobservedatasite58kb
downstream. Silent loops are now detected between
the sites at +5 kb and 58 kb, whereas interactions
between the sites at 114kband +5 kb are largely
lost.TheGATA-1-boundsiteat58kblacksenhancer
activity,andenhanceractivityofthe 114kbsiteis
considerably lower
46
(Figure 3(e)). The mechanism
behind this selective loop formation is unknown,
but the looping afnities may differ depending on
which GATA-factor is bound. The silent chromatin
loop between the nonenhancing sites at 5kb and
58 kb may act as a distraction from the moderately
enhancingsiteat114kbthough.Hereagain,formal
evidenceforthismechanismcouldbeobtainedfrom
3C experiments in cells where the site at 58 kb has
looping. One example of potential distracting loops
occurs at the imprinted mouse Dlx5/Dlx6 locus
45
(Figure 3(d)). The Dlx5 gene is maternally expressed
in brain and lymphoid tissue, but is bi-allelically
expressed in individuals with MECP2 mutations
(methyl-CpG binding protein 2). In mice, MECP2
binds several regions within this locus, although
methylation does not seem to be imprinted. In
WT mice, the Dlx5 gene loops toward the Dlx6
gene,whichcontainsastrongMECP2bindingsite
45
(Figure3(d)), a loopthat is not detectedin Mecp2-null
mice. A combination of ChIP and 3C revealed that
the loop only occurs when the MECP2 bound region
ismarkedbyrepressiveH3K9me2histonemarks.In
WTandMecp2-nullmice,twoadditionalactiveloops
aredetectedbetweentheDlx5geneandtwoupstream
regions carryingactive histone H3acetylation marks
45
(Figure 3(d)). These data suggest that the paternal
andmaternalallelesformalternativesilentandactive
loops. While the MECP2 bound region involved in
the silent loop carries repressive marks, it is has not
been demonstrated that this loop actively silences
the Dlx5 gene. Alternatively, this loop may distract
the Dlx5 gene from interacting with the distant H3
3C experiments in cells where the site at 58 kb has
beendeleted.
Alastexampleofalternativealthoughexclu-
sivelyactiveloopsoccursattheimprintedIgf2/H19
locus http://learn.genetics.utah.edu/content/epigeneti
cs/imprinting/,whichisinvolvedinembryonicgrowth
(Figure 3(f)F). The Igf2 gene encodes the insulin-like
growth factor 2 and is paternally expressed, whereas
the lincRNA H19 is maternally expressed. The locus
contains three paternally methylated DMRs (differ-
entially methylated region). One of these DMRs is
located near theH19promoterandguidesimprinted
activity through selective CTCF and Cohesin bind-
ingandalternativechromatinlooping.
25,47,48
At the
maternalallele,thisDMRisnonmethylatedandbinds
CTCF. CTCF mediates chromatin looping between
thisH19DMRandaDMRupstreamofthemainIgf2
transcriptional start.
49
The enhancers nearH19 acti-
vatethisgeneandIgf2isinsulatedinaseparateloop
(Figure 3(f)). The paternal H19DMRismethylated,
unboundbyCTCFandformsanalternativeloopwith
the DMR downstream of the Igf2 gene.
49
On the
paternal allele, the H19 gene is silenced due to its
methylation,butIgf2isactivatedduetoitsproximity
Vol ume2, September/ October2013 2013Wi l eyPer i odi cal s, I nc. 623

AdvancedReview wires.wiley.com/devbio
totheenhancers(Figure3(f)).Interestingly,the H19
lincRNA contains a miRNA that negatively regulates
Igf1r abundance.
50
Igf2 is the main ligand of Igf1r,
and therefore H19 indirectly antagonizes Igf2 func-
tion.Asaresult,thealternativeloopsattheIgf2H19
locushaveopposinginuencesonembryonicgrowth.
COLINEARACTIVATIONOFHOX
GENESIN3D
Hox genes encode proteins that organize patterns
inthedevelopingembryo.
51
Hox genes http://www.
nature.com/scitable/topicpage/hox-genes-in-developm
ent-the-hox-code-41402 are active in different,
although often overlapping, domains that provide
cellular identities by activating downstream devel-
opmentalprograms.Thiscomplextaskrequiresthese
genes to be tightly regulated at the transcriptional
level. Their coordinated expression is mediated, at
leastpartially,bytheirgenomicorganization,amech-
anism known as colinearity.
52
The 39 mammalian
Hox genes are located in four genomic clusters and
the relative position of each gene within its own clus-
ter determines its pattern of activation in time and
space (Figure 4(a) for the HoxD cluster). These col-
inear transcriptional programs are accompanied by
dynamic chromatin looping and overall changes in
3Dchromatinorganization.
In developing mouse digits, the activation
of Hoxd genes follows a quantitative gradient,
from highest transcription for Hoxd13 to lowest
Hoxd9 (Figure4(b) and Ref 53). Previously, two
regulatory regions (Prox and GCR), located in the
5
(centromeric) gene desert were proposed to guide

gene expression in developing digits.
54,55
Recently,
3Cexperimentsconrmedtheexistenceofchromatin
loops between the Hoxd13 gene and these two
regulatory regions.
56
Unexpectedly though, induced
rearrangements within the HoxD cluster and the
5
gene desert indicated that correct Hoxd gene

activation in digits requires additional sequences
located within the 5
gene desert. A 4C based

study identiedve additional distant elements, which
contact the active Hoxd13 gene in addition to Prox
andGCR
56
(Figure4(a),blackstars;Figure4(c),left).
Inthiscase,functionalandgeneticevidences in vivo
have conrmed the importance of these interactions.
The combined(althoughnot necessarily simultaneous)
action of these elements provides guidance for digit
development. In embryonic brain, a prestructure is
detected that consists of loops between the Hoxd13
gene and three out of these seven distant regions
56
(Figure4(c), right). The overall pattern of long-
range contacts displays a similar polar pattern,
independently fromthe state of activity. Genes located
on the 5
side of the cluster preferably contact

sequences in the 5
desert, whereas silent genes

located on the 3
side contact sequences in the 3
neighborhoodof thegene cluster.

56
Scanning deletions
within the 5
genedesert,encompassinganincreasing
number of these regulatory regions, have additive
effectsondigitdevelopment.
56
Analogoustoshadow
enhancersinDrosophila,
57
theseregulatoryelements
may provide regulatory robustness. Alternatively,
interactions with the regulatory regions may be
restricted to one gene at a time, similar to the -
globinLCR.
58
Several regulatory elements maythus be
requiredfor simultaneousactivation of all target Hoxd
genes.
Next to long-range chromatin loops, local
3D chromatin dynamics accompanies Hox gene
activation. InactiveHoxclustersinmouseembryonic
brain are organized as distinct 3D compartments,
as shown by 4C
59
(Figure4(d) and (f) for the
HoxDcluster). These compartments preciselycoincide
with the domain of repressive histone H3K27me3
marks that decorate the clusters, suggesting a
mechanistic relationship. The result of this 3D
organization is a physical separation of H3K27me3
markedchromatin,carryingtheinactive Hox genes,
from the surrounding gene deserts. Along the AP-
axis in the developing embryo, Hox genes are
sequentially activated from the 3
-end in both time

and space. This temporal and spatial colinearity
is accompanied by extensive remodeling of histone
modications.
59,60
Recently, 4C was used to study
changes in 3D organization accompanying spatial
colinearactivation.
59
Abimodal3Dorganizationwas
detected in tissues where 3
-located Hox genes are

active, but 5
-located genes remain silent. Inactive

genes remain covered by repressive H3K27me3
marks, whereas active genes now carry the active
H3K4me3 mark. Similarly, a discrete inactive 3D
compartment remains, nowcontaining only 5
-located
genes. Interestingly, active genes are also contained
within a 3D compartment and this precisely overlaps
with the H3K4me3 marked domain (Figure4(e)
and (f), for HoxD cluster with active Hoxd1 to
Hoxd8 genes).
59
The correlation between the 3D
organization and the epigenetic marks at Hox
clusters is therefore a common mechanism for both
repressive H3K27me3 and active H3K4me3 marks.
This bimodal 3D organization results in a physical
separation, not only between domains carrying
repressive and active chromatin marks, but also from
the neighboring chromatin (Figure4(f)). The size
of active and inactive domains at the Hox cluster
coincides with the number of active and inactive
624 2013Wi le y Per i odi cal s, I nc. Volume 2, S ept embe r/Oc tobe r 2013

genes
59
and similar domains were detected during
digitdevelopment.
56
3Dcompartmentalizationof H3K27me3marked
chromatin may be a common phenomenon as it is
detected at the mouseDlx1/Dlx2 locus,
59
the human
GATA-4 locus
61
and the Drosophila Antennapedia
andBithoraxcomplexes.
62
4Csignalswithintheinac-
tive Hox compartments show moderate variation,
indicating that fragments can all interact among each
other.
59
Additionally, CTCF has been proposed to
structure 3D organization of inactive humanHOXA
clusters.
63,64
CTCF binds several positions withinHox
clusters,butbindingismostlyindependentofcelltype
(e.g., Refs 3 and 6365). Modeling of 3D organiza-
tioninembryoniccarcinomacellssuggeststhatCTCF
sites may act as scaffolding at the inactive HOXA
locus.
63
In a lung broblast cell line, CTCF and the
Cohesin complex are proposedtospatially connect the
bordersoftheH3K27me3markeddomain.
64
How-
ever, gene regulation at the HoxD cluster (as well
as throughout chromosome 2) in limb buds lacking
CTCFhasfailedtorevealasubstantialeffectinterms
ofinsulationcapacity.
66
So far, 3D compartmental-
izationofH3K4me3markedchromatinhasonlybeen
observed at mouse Hox clusters during embryonic
development
56,59
and in the humanHOXAclusterin
broblastcells.
67
H3K4me3atHoxclustersisspeci-
callydepositedbytheMLL1/MLL2complexes
68
and
in a human cell line where several HOXAgenesare
activated,MLLcomplexesseemtoberecruitedbya
noncodingRNA.
67,69
DepletionofthisRNAstrongly
reducesthepresenceofH3K4me3andMLLcomplex
ontheactivegenes,buthasverymoderateeffectson
3Dorganization. 3Dorganizationof activeHox genes
thusmaybeupstreamofthesefactors.
In summary, different colinear activation
programs of Hoxgenesareaccompaniedbyspecic
long-range chromatin interactions
56
and dynamic,
active and inactive, local 3D compartments.
56,59
Although the function of long-range chromatin loops
hasbeenwellestablishedatmanyloci,thefunctionof
chromatin compartmentalization is less understood.
Inactive compartments, also detected at several
non-Hox loci, may concentrate repressive factors
and block potential inuences from neighboring
chromatin, thus improving regulatory robustness.
Active compartments, sofar only detected at Hox loci,
mayhaveseveralfunctions.Besidestheconcentration
of activating factors, they may promote recycling
of the transcription machinery and, in the case
of quantitative transcriptional variations, provide
priorities amongst active genes for interactions with
long-range regulatory elements. Finally, at the Hox
gene loci, dynamic 3D compartmentalization may
allow proper 3
to 5
activation sequence during

temporal colinearity and x transcription patterns
alongthedevelopingembryonicAP-axis.Howthese
mechanisms are dynamically organized remains to be
determined.
CONCLUSION
Over the past few years, dynamic 3D chromatin
interactions have been described at many gene
loci. Transcriptional activation may be accompanied
by the formation of chromatin loops between
genesandenhancers.Similarly,chromatinloopsare
observedbetweenCTCFandCohesincomplexbound
insulators, which may have functions that are either
structural (at the -globin locus
21,23
) or regulatory
(at the Igf2/H19 locus
49
). Looping also occurs at
transcriptionally inactive loci where prestructures
are sometimes found that partially recapitulate the
3D conformation of the active state. Two different
types of prestructures are described: (1)structures
isolating a locus from its environment (e.g., at the
-globin locus
21,23
) and (2) structures that facilitate
future promoterenhancer contacts over very long
distance (e.g., at the Shh
40
and the HoxD
56
loci).
Whether chromatin loops in mammalian cells can
actively mediate repression over a distance remains
to be determined, since functional and/or genetic
evidence for a silencing function of looping is still
lacking. An alternative explanation for the reported
silentloopsmaybethetetheringofgenesawayfrom
surroundingenhancers.Theuseof3C-liketechniques
in these experiments provides a population wide
averagedescriptionof3Dorganization.Inmostcases,
data from (high-resolution) FISH or other imaging
techniqueswillberequiredforafullunderstandingof
dynamics at the single cell level.
Animportantchallengetounderstand3Dchro-
matinorganization isthe identicationofmechanisms
underlying chromatin looping. Transcription factors,
co-factors,insulatorproteins,noncodingRNAsand
epigenetic marks have all been implicated in this pro-
cess. Interesting insights about the interplay between
transcription factors and co-factors were recently
obtained fortheerythroidtranscriptionfactorGATA-
1 and its co-factor LDB1. Chromatin looping and
transcriptional activity are strongly reduced in GATA-
1 null cells.
29
Re-establishmentofchromatinloops,
using articial LDB1tethering, onlyrestores transcrip-
tion up to 20%,
31
suggesting a direct requirement
for GATA-1. In contrast, transcription is similarly
increasedwhen full LDB1or only its self-association
domainis tethered
31
Therefore, LDB1 seems tofunc-
tionsolelyinformingchromatinlooping(althoughan

(a)
ChromosomalPosition(Mb)
6 . 4 7 5 . 4 7
3 4 1 1 12 13 1 8 9 10 Evx2
ChromosomalPosition(Mb)
74.0 75.0
HoxDcluster
Mouse HoxDcluster
Hoxd-gene:
x o r P I GCR V IV III II
(b) Long-rangechromatinloopingindevelopingdigits (c)
11 12 8 3 1 9 10 Evx2
Expressionindevelopingdigits
100%
50%
0%
E
x
p
r
e
s
s
i o
n
l e
v
e
l
(
r
e
l a
t i v
e
t o
H
o
x
d
1
3
)
H o x D
5 3
P
rox
I
I V
,V
G
C
R
II
I I I
H o x D
I
V
II III
IV
GCR
Prox
Developingdigitcells
(expressing)
Braincells
(nonexpressing)
6 . 4 7 5 . 4 7
3 11 4 13 1 9 Evx2
H3K27me3
H3K4me3
(d)
Inactive3Dorganization
Hoxd13
Hoxd4
4C-seq
ChIP-seq
6 . 4 7 5 . 4 7
3 11 4 13 1 9 Evx2
H3K27me3
H3K4me3
Hoxd13
Hoxd4
4C-seq
ChIP-seq
(e)
Partiallyactive3Dorganization
(f)
Local3Dorganization
Inactive3D
organization
Partiallyactive3D
organization
FI GURE 4 |3DchromatinorganizationofmammalianHoxloci.(a)GenomicorganizationofthemouseHoxDclusterandgenomicenvironment.
Top:theHoxDclusterisankedbytwogenedeserts.TheHoxDclusterisindicatedinred,othergenesingreyandthelocationofregulatoryregions
indevelopingdigitsisindicatedbyblackstars.Bottom:enlargementofthe HoxDcluster,withindividualHoxdgenesindicatedinred.(b)Expression
patternofHoxdgenesindevelopingdigits.Absoluteexpressionlevelsareprovidedrelativeto Hoxd13levels.Panelcompiledfromdatapresentedin
Ref.53.Copyright2008ColdSpringHarborLaboratoryPress.(c)Schematicillustrationoflong-rangechromatinloopingattheHoxDclusterin
developingdigits(left)andnon-expressingbraincells(right).(d)Local3DorganizationofthemouseHoxDclusterininactivemousebraincells.4C
signalwithviewpointsHoxd13andHoxd4(greybars)displaysthesamebordersastherepressiveH3K27me3ChIP-seqsignal.Inactivegenesare
indicatedinred.PanelcompiledfromdatapresentedinRef.59.Copyright2011AmericanAssociationfortheAdvancementofScience.(e)Local3D
organizationofthemouseHoxDclusterincellsalongtheprimaryAP-axiswhereHoxdgeneactivityisdetecteduptoHoxd8.The4Csignalwiththe
inactiveHoxd13viewpointdisplaysthesamebordersastherepressiveH3K27me3ChIP-seqsignal,whereasthe4Csignalwiththeactive Hoxd4
viewpointdisplaysthesamebordersastheactiveH3K4me3ChIP-seqsignal.Inactivegenesareindicatedinredandactivegenesinblue.Panel
compiledfromdatapresentedinRef.59.Copyright2011AmericanAssociationfortheAdvancementofScience.(f)Schematicrepresentationofthe
dynamic3DorganizationofthemouseHoxDclusteralongtheprimaryAP-axis.Inactivegenesareindicatedinredandactivegenesinblue.Top:In
inactivebraincells,theHoxDclusterisorganizedasasingle3DcompartmentthatseparatestheH3K27me3markedchromatinfromitssurroundings.
Bottom:thepartiallyactivatedHoxDclusteralongtheAP-axisadoptsabimodalorganization,separatingactiveandinactivechromatinfromeach
other,aswellasfromtheirsurroundings.

inuenceofLCRboundendogenousLDB1cannotbe
excluded).Asimilarinterplayisobservedbetweenthe
CTCF protein, the Cohesin complex and members of
the Mediator complex. CTCF has been implicated in
chromatin looping at many genomic loci (see above
and in Refs 23, 49, and 64). Two studies simultane-
ously reported that the Cohesin complex co-occupies
6090% of CTCF binding sites in human cells
24,25
siRNA-mediated knockdown of CTCF specically
reduces the occupancy of the Cohesin complex at
CTCF binding sites, but does not inuence general
loading of the complex to chromosomes
24,25
Con-
versely, knockdown of the Cohesin complex member
SSC1/RAD21hasnoeffectonCTCFbinding.Rather
thandirectlyfunctionasaninsulatorprotein,CTCF
may thus position the Cohesin complex at dened
positions in the genome. The Cohesin complex may
theninturnberesponsiblefortheformationofchro-
matin loops, a functionthat bears some similarity with
its role during mitotic and meiotic sister-chromatid
cohesion.IndeedtheknockdownoftheSSC1/RAD21
abrogates both imprinting at the human IGF2/H19
locus and chromatin looping at the human IFNG
locus, without affecting CTCF location.
25,69,70
In
addition, the Mediator complex has been involved in
positioningtheCohesincomplexandchromatinloop-
ingbetweengenesandenhancers.
70
Thegeneralfunc-
tion of the Cohesin complex during interphase may
thusbetheformationofchromatinloopsanditsasso-
ciationwithotherfactorsmayprovidespecicityfor
interaction partners. Elucidating such dependencies
among the many factors involved in chromatin loop-
ing will therefore be important for the understanding
ofthespecicityanddynamicsofchromatinloops.
Another as yet poorly understood aspect of
chromatinloopingishowinteractionpartnersnd
eachother.Highlystablechromatininteractionsare
detectedinupto10%of the cells between the -globin
genes and the -globin LCR, when both are located
ondifferentchromosomes.
71
Interveningchromatinis
therefore not absolutely required for the formation
of chromatin interactions. Proximity of two genomic
elements on the same chromosome will also promote
spatial proximity in the nuclear space, thus strongly
increasingthechanceofndingeachother.Efcient
loopformationmaybefurtherfacilitatedbythepres-
ence of prestructures acting as scaffolds. Additional
insights may come from ndings that the mouse,
human and Drosophila genomes have an exten-
sively compartmentalized 3D architecture.
15,16,59,72
In a recent study, topological domains
16
(a specic
class of 3D compartments) are proposed to repre-
sent enhancerpromoter units (EPUs).
4
Within EPUs,
genes and their cell type-specic enhancers are con-
tained. Such a compartmentalization may provide an
explanation for several observations: (1) how loop-
ing is directed toward correct interactions partners,
(2)why CTCF binding and insulator looping are
highly constitutive,
3,21,23,65
(3) why prestructures are
present at inactive loci, as they may represent con-
stitutive contacts that structure EPUs, and (4)why
alternative loops are observed, as they may either
also be structuring loops or act to avoid unwanted
contacts within EPUs. Future studies should reveal
whether or not 3D compartments demarcate EPUs
and if they actively play a role in enhancergene
looping.
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6/24/2014 Chromatin looping and organization at developmentally regulated gene loci | Daan Noordermeer - Academia.

(centromeric) gene desert were proposed to guide

gene desert indicated that correct Hoxd gene

gene desert. A 4C based

side of the cluster preferably contact

desert, whereas silent genes

side contact sequences in the 3

neighborhoodof thegene cluster.

-end in both time

-located Hox genes are

-located genes remain silent. Inactive

activation sequence during

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