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

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

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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) regions together.

43 Triplecolor FISH experiments were used to determine the3D organization in single cells, although the use of uorescent probes restricted the number of viewpointsthat could be addressed within the locus. Modeling of these interactions in the two developmentally differentcell types showed that the Igh locus becomes morecompacted prior to recombination. However, withinthis 3D structure, the different regions obtain morefreedom to interact with each other. As such, the 3Dorganization of this prestructure may prepare the Ighlocus for maximum diversity of interactions duringthe later recombination stage.

Silent and Alternative Loops: Distraction orRepression?While many examples of chromatin loops involvingenhancers and insulators are known, denitiveevidence for chromatin loops, which would directlysilence genes is, to our knowledge, lacking.Interestingly, at two Drosophila loci, the Snailrepressor actively inhibits the formation of activeloops, a mechanism coined anti-looping.44 Similarly,silent chromatin loops at mammalian loci may act bydistracting genes from forming active loops, whichmay lead to the same regulatory outcome as anti-looping. One example of potential distracting loops

acetylated marked regions, which may potentiallyhave enhancer activities. Deletion studies, combinedwith 3C experiments should provide a distinctionbetween these hypotheses.

In mouse erythroid cells, the Kit locus provides asimilar example of alternative active and silent loops46

(Figure 3(e)). The active Kit locus is bound at two sitesby GATA-2, when GATA-1 is absent, as determinedin a GATA-1 inducible cell line (see Building a -globin ACH and Ref 29). When bound by GATA-2,an upstream enhancer (114 kb) forms a chromatinloop with a site located 5 kb downstream (+5 kb)from the Kit transcriptional start site46 (Figure 3(e)).When GATA-1 is present in the nucleus, the Gata2 andKit genes are repressed. Instead of GATA-2, GATA-1now binds both the 114 kb and +5 kb sites, while

additional GATA-1 binding is observed at a site 58 kbdownstream. Silent loops are now detected betweenthe sites at +5 kb and 58 kb, whereas interactionsbetween the sites at 114 kb and +5 kb are largelylost. The GATA-1-bound site at 58 kb lacks enhanceractivity, and enhancer activity of the 114 kb site isconsiderably lower46 (Figure 3(e)). The mechanismbehind this selective loop formation is unknown,but the looping afnities may differ depending onwhich GATA-factor is bound. The silent chromatinloop between the nonenhancing sites at 5 kb and58 kb may act as a distraction from the moderatelyenhancing site at 114 kb though. Here again, formalevidence for this mechanism could be obtained from3C experiments in cells where the site at 58 kb has



looping. One example of potential distracting loopsoccurs at the imprinted mouse Dlx5 / Dlx6 locus45

(Figure 3(d)). The Dlx5 gene is maternally expressedin brain and lymphoid tissue, but is bi-allelicallyexpressed in individuals with MECP2 mutations(methyl-CpG binding protein 2). In mice, MECP2binds several regions within this locus, althoughmethylation does not seem to be imprinted. InWT mice, the Dlx5 gene loops toward the Dlx6gene, which contains a strong MECP2 binding site45

(Figure 3(d)), a loop that is not detected in Mecp2-nullmice. A combination of ChIP and 3C revealed thatthe loop only occurs when the MECP2 bound regionis marked by repressive H3K9me2 histone marks. InWT and Mecp2-null mice, two additional active loopsare detected between the Dlx5 gene and two upstreamregions carrying active histone H3 acetylation marks45

(Figure 3(d)). These data suggest that the paternal

and maternal alleles form alternative silent and activeloops. While the MECP2 bound region involved inthe silent loop carries repressive marks, it is has notbeen demonstrated that this loop actively silencesthe Dlx5 gene. Alternatively, this loop may distractthe Dlx5 gene from interacting with the distant H3

3C experiments in cells where the site at 58 kb hasbeen deleted.

A last example of alternativealthough exclu-sively activeloops occurs at the imprinted Igf2 / H19locus http://learn.genetics.utah.edu/content/epigenetics/imprinting/, which is involved in embryonic growth(Figure 3(f)F). The Igf2 gene encodes the insulin-likegrowth factor 2 and is paternally expressed, whereasthe lincRNA H19 is maternally expressed. The locuscontains three paternally methylated DMRs (differ-entially methylated region). One of these DMRs islocated near the H19 promoter and guides imprintedactivity through selective CTCF and Cohesin bind-ing and alternative chromatin looping.25,47,48 At thematernal allele, this DMR is nonmethylated and bindsCTCF. CTCF mediates chromatin looping betweenthis H19 DMR and a DMR upstream of the main Igf2transcriptional start.49 The enhancers near H19 acti-

vate this gene and Igf2 is insulated in a separate loop(Figure 3(f)). The paternal H19 DMR is methylated,unbound by CTCF and forms an alternative loop withthe DMR downstream of the Igf2 gene.49 On thepaternal allele, the H19 gene is silenced due to itsmethylation, but Igf2 is activated due to its proximity

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to the enhancers (Figure 3(f)). Interestingly, the H19lincRNA contains a miRNA that negatively regulatesIgf1r abundance.50 Igf2 is the main ligand of Igf1r,and therefore H19 indirectly antagonizes Igf2 func-tion. As a result, the alternative loops at the Igf2H19

locus have opposing inuences on embryonic growth.

COLINEAR ACTIVATION OF HOX GENES IN 3D

Hox genes encode proteins that organize patternsin the developing embryo.51 Hox genes http://www.nature.com/scitable/topicpage/hox-genes-in-development-the-hox-code-41402 are active in different,although often overlapping, domains that providecellular identities by activating downstream devel-opmental programs. This complex task requires thesegenes to be tightly regulated at the transcriptionallevel. Their coordinated expression is mediated, atleast partially, by their genomic organization, a mech-anism known as colinearity.52 The 39 mammalian

Hox genes are located in four genomic clusters andthe relative position of each gene within its own clus-ter determines its pattern of activation in time andspace (Figure 4(a) for the HoxD cluster). These col-inear transcriptional programs are accompanied bydynamic chromatin looping and overall changes in3D chromatin organization.

In developing mouse digits, the activationof Hoxd genes follows a quantitative gradient,from highest transcription for Hoxd13 to lowestHoxd9 (Figure 4(b) and Ref 53). Previously, tworegulatory regions (Prox and GCR), located in the5 (centromeric) gene desert were proposed to guidegene expression in developing digits.54,55 Recently,3C experiments conrmed the existence of chromatinloops between the Hoxd13 gene and these two

regulatory regions.56 Unexpectedly though, inducedrearrangements within the HoxD cluster and the5 gene desert indicated that correct Hoxd geneactivation in digits requires additional sequenceslocated within the 5 gene desert. A 4C basedstudy identied ve additional distant elements, whichcontact the active Hoxd13 gene in addition to Proxand GCR56 (Figure 4(a), black stars; Figure 4(c), left).In this case, functional and genetic evidences in vivohave conrmed the importance of these interactions.The combined (although not necessarily simultaneous)action of these elements provides guidance for digitdevelopment. In embryonic brain, a prestructure isdetected that consists of loops between the Hoxd13gene and three out of these seven distant regions56

(Figure 4(c), right). The overall pattern of long-

range contacts displays a similar polar pattern,

independently from the state of activity. Genes locatedon the 5 side of the cluster preferably contactsequences in the 5 desert, whereas silent geneslocated on the 3 side contact sequences in the 3

neighborhood of the gene cluster.56 Scanning deletions

within the 5 gene desert, encompassing an increasingnumber of these regulatory regions, have additiveeffects on digit development.56 Analogous to shadowenhancers in Drosophila,57 these regulatory elementsmay provide regulatory robustness. Alternatively,interactions with the regulatory regions may berestricted to one gene at a time, similar to the -globin LCR.58 Several regulatory elements may thus berequired for simultaneous activation of all target Hoxd genes.

Next to long-range chromatin loops, local3D chromatin dynamics accompanies Hox geneactivation. Inactive Hox clusters in mouse embryonicbrain are organized as distinct 3D compartments,as shown by 4C59 (Figure 4(d) and (f) for theHoxD cluster). These compartments precisely coincide

with the domain of repressive histone H3K27me3marks that decorate the clusters, suggesting amechanistic relationship. The result of this 3Dorganization is a physical separation of H3K27me3marked chromatin, carrying the inactive Hox genes,from the surrounding gene deserts. Along the AP-axis in the developing embryo, Hox genes aresequentially activated from the 3-end in both timeand space. This temporal and spatial colinearityis accompanied by extensive remodeling of histonemodications.59,60 Recently, 4C was used to studychanges in 3D organization accompanying spatialcolinear activation.59 A bimodal 3D organization wasdetected in tissues where 3-located Hox genes areactive, but 5-located genes remain silent. Inactivegenes remain covered by repressive H3K27me3

marks, whereas active genes now carry the activeH3K4me3 mark. Similarly, a discrete inactive 3Dcompartment remains, now containing only 5-locatedgenes. Interestingly, active genes are also containedwithin a 3D compartment and this precisely overlapswith the H3K4me3 marked domain (Figure 4(e)and (f), for HoxD cluster with active Hoxd1 toHoxd8 genes).59 The correlation between the 3Dorganization and the epigenetic marks at Hoxclusters is therefore a common mechanism for bothrepressive H3K27me3 and active H3K4me3 marks.This bimodal 3D organization results in a physicalseparation, not only between domains carryingrepressive and active chromatin marks, but also fromthe neighboring chromatin (Figure 4(f)). The sizeof active and inactive domains at the Hox cluster

coincides with the number of active and inactive

624 2 0 13 W i le y P er i od i ca l s, I n c. V o lu me 2, S ep t em be r/O c to be r 2 0 13




genes59 and similar domains were detected duringdigit development.56

3D compartmentalization of H3K27me3 markedchromatin may be a common phenomenon as it isdetected at the mouse Dlx1 / Dlx2 locus,59 the humanGATA-4 locus61 and the Drosophila Antennapediaand Bithorax complexes.62 4C signals within the inac-tive Hox compartments show moderate variation,indicating that fragments can all interact among eachother.59 Additionally, CTCF has been proposed to

structure 3D organization of inactive human HOXAclusters.63,64 CTCF binds several positions within Hoxclusters, but binding is mostly independent of cell type(e.g., Refs 3 and 6365). Modeling of 3D organiza-tion in embryonic carcinoma cells suggests that CTCFsites may act as scaffolding at the inactive HOXAlocus.63 In a lung broblast cell line, CTCF and theCohesin complex are proposed to spatially connect theborders of the H3K27me3 marked domain.64 How-ever, gene regulation at the HoxD cluster (as wellas throughout chromosome 2) in limb buds lackingCTCF has failed to reveal a substantial effect in termsof insulation capacity.66 So far, 3D compartmental-ization of H3K4me3 marked chromatin has only beenobserved at mouse Hox clusters during embryonicdevelopment56,59 and in the human HOXA cluster in

broblast cells.67 H3K4me3 at Hox clusters is speci-cally deposited by the MLL1/MLL2 complexes68 andin a human cell line where several HOXA genes areactivated, MLL complexes seem to be recruited by anoncoding RNA.67,69 Depletion of this RNA stronglyreduces the presence of H3K4me3 and MLL complexon the active genes, but has very moderate effects on3D organization. 3D organization of active Hox genesthus may be upstream of these factors.

In summary, different colinear activationprograms of Hox genes are accompanied by speciclong-range chromatin interactions56 and dynamic,active and inactive, local 3D compartments.56,59

Although the function of long-range chromatin loopshas been well established at many loci, the function of chromatin compartmentalization is less understood.

Inactive compartments, also detected at severalnon-Hox loci, may concentrate repressive factorsand block potential inuences from neighboringchromatin, thus improving regulatory robustness.Active compartments, so far only detected at Hox loci,may have several functions. Besides the concentrationof activating factors, they may promote recyclingof the transcription machinery and, in the caseof quantitative transcriptional variations, providepriorities amongst active genes for interactions withlong-range regulatory elements. Finally, at the Hoxgene loci, dynamic 3D compartmentalization may

allow proper 3 to 5 activation sequence duringtemporal colinearity and x transcription patternsalong the developing embryonic AP-axis. How thesemechanisms are dynamically organized remains to bedetermined.

CONCLUSION

Over the past few years, dynamic 3D chromatininteractions have been described at many gene

loci. Transcriptional activation may be accompaniedby the formation of chromatin loops betweengenes and enhancers. Similarly, chromatin loops areobserved between CTCF and Cohesin complex boundinsulators, which may have functions that are eitherstructural (at the -globin locus21,23) or regulatory(at the Igf2 / H19 locus49). Looping also occurs attranscriptionally inactive loci where prestructuresare sometimes found that partially recapitulate the3D conformation of the active state. Two differenttypes of prestructures are described: (1) structuresisolating a locus from its environment (e.g., at the-globin locus21,23) and (2) structures that facilitatefuture promoterenhancer contacts over very longdistance (e.g., at the Shh40 and the HoxD56 loci).Whether chromatin loops in mammalian cells can

actively mediate repression over a distance remainsto be determined, since functional and/or geneticevidence for a silencing function of looping is stilllacking. An alternative explanation for the reportedsilent loops may be the tethering of genes away fromsurrounding enhancers. The use of 3C-like techniquesin these experiments provides a population wideaverage description of 3D organization. In most cases,data from (high-resolution) FISH or other imagingtechniques will be required for a full understanding of dynamics at the single cell level.

An important challenge to understand 3D chro-matin organization is the identication of mechanismsunderlying chromatin looping. Transcription factors,co-factors, insulator proteins, noncoding RNAs andepigenetic marks have all been implicated in this pro-

cess. Interesting insights about the interplay betweentranscription factors and co-factors were recentlyobtained for the erythroid transcription factor GATA-1 and its co-factor LDB1. Chromatin looping andtranscriptional activity are strongly reduced in GATA-1 null cells.29 Re-establishment of chromatin loops,using articial LDB1 tethering, only restores transcrip-tion up to 20%,31 suggesting a direct requirementfor GATA-1. In contrast, transcription is similarlyincreased when full LDB1or only its self-associationdomainis tethered31 Therefore, LDB1 seems to func-tion solely in forming chromatin looping (although an



(a)

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(f)Local 3D organization

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F I G U R E 4 | 3D chromatin organization of mammalian Hox loci. (a) Genomic organization of the mouse HoxD cluster and genomic environment.

Top: the HoxD cluster is anked by two gene deserts. The HoxD cluster is indicated in red, other genes in grey and the location of regulatory regions

in developing digits is indicated by black stars. Bottom: enlargement of the HoxD cluster, with individual Hoxd genes indicated in red. (b) Expression

pattern of Hoxd genes in developing digits. Absolute expression levels are provided relative to Hoxd13 levels. Panel compiled from data presented in

Ref. 53. Copyright 2008 Cold Spring Harbor Laboratory Press. (c) Schematic illustration of long-range chromatin looping at the HoxD cluster in

developing digits (left) and non-expressing brain cells (right). (d) Local 3D organization of the mouse HoxD cluster in inactive mouse brain cells. 4C

signal with viewpoints Hoxd13 and Hoxd4 (grey bars) displays the same borders as the repressive H3K27me3 ChIP-seq signal. Inactive genes are

indicated in red. Panel compiled from data presented in Ref. 59. Copyright 2011 American Association for the Advancement of Science. (e) Local 3D

organization of the mouse HoxD cluster in cells along the primary AP-axis where Hoxd gene activity is detected up to Hoxd8 . The 4C signal with the

inactive Hoxd13 viewpoint displays the same borders as the repressive H3K27me3 ChIP-seq signal, whereas the 4C signal with the active Hoxd4

viewpoint displays the same borders as the active H3K4me3 ChIP-seq signal. Inactive genes are indicated in red and active genes in blue. Panelcompiled from data presented in Ref. 59. Copyright 2011 American Association for the Advancement of Science. (f) Schematic representation of the

dynamic 3D organization of the mouse HoxD cluster along the primary AP-axis. Inactive genes are indicated in red and active genes in blue. Top: In

inactive brain cells, the HoxD cluster is organized as a single 3D compartment that separates the H3K27me3 marked chromatin from its surroundings.

Bottom: the partially activated HoxD cluster along the AP-axis adopts a bimodal organization, separating active and inactive chromatin from each

other, as well as from their surroundings.



inuence of LCR bound endogenous LDB1 cannot beexcluded). A similar interplay is observed between theCTCF protein, the Cohesin complex and members of the Mediator complex. CTCF has been implicated in

chromatin looping at many genomic loci (see aboveand in Refs 23, 49, and 64). Two studies simultane-ously reported that the Cohesin complex co-occupies6090% of CTCF binding sites in human cells24,25

siRNA-mediated knockdown of CTCF specicallyreduces the occupancy of the Cohesin complex atCTCF binding sites, but does not inuence generalloading of the complex to chromosomes24,25 Con-versely, knockdown of the Cohesin complex memberSSC1/RAD21 has no effect on CTCF binding. Ratherthan directly function as an insulator protein, CTCFmay thus position the Cohesin complex at denedpositions in the genome. The Cohesin complex maythen in turn be responsible for the formation of chro-matin loops, a function that bears some similarity withits role during mitotic and meiotic sister-chromatid

cohesion. Indeed the knockdown of the SSC1/RAD21abrogates both imprinting at the human IGF2 / H19locus and chromatin looping at the human IFNGlocus, without affecting CTCF location.25,69,70 Inaddition, the Mediator complex has been involved inpositioning the Cohesin complex and chromatin loop-ing between genes and enhancers.70 The general func-tion of the Cohesin complex during interphase maythus be the formation of chromatin loops and its asso-ciation with other factors may provide specicity forinteraction partners. Elucidating such dependenciesamong the many factors involved in chromatin loop-ing will therefore be important for the understandingof the specicity and dynamics of chromatin loops.

Another as yet poorly understood aspect of chromatin looping is how interaction partners ndeach other. Highly stable chromatin interactions aredetected in up to 10% of the cells between the -globin

genes and the -globin LCR, when both are locatedon different chromosomes.71 Intervening chromatin istherefore not absolutely required for the formationof chromatin interactions. Proximity of two genomicelements on the same chromosome will also promotespatial proximity in the nuclear space, thus stronglyincreasing the chance of nding each other. Efcientloop formation may be further facilitated by the pres-ence of prestructures acting as scaffolds. Additionalinsights 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 domains16 (a specicclass 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 anexplanation for several observations: (1) how loop-ing is directed toward correct interactions partners,(2) why CTCF binding and insulator looping arehighly constitutive,3,21,23,65 (3) why prestructures arepresent at inactive loci, as they may represent con-stitutive contacts that structure EPUs, and (4) whyalternative loops are observed, as they may eitheralso be structuring loops or act to avoid unwantedcontacts within EPUs. Future studies should revealwhether or not 3D compartments demarcate EPUsand if they actively play a role in enhancergenelooping.

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