REVIEW

Chromatin plasticity: A versatilelandscape that underlies cell fateand identityTejas Yadav, Jean-Pierre Quivy, Geneviève Almouzni*

During development and throughout life, a variety of specialized cells must begenerated to ensure the proper function of each tissue and organ. Chromatin playsa key role in determining cellular state, whether totipotent, pluripotent, multipotent,or differentiated. We highlight chromatin dynamics involved in the generationof pluripotent stem cells as well as their influence on cell fate decision andreprogramming. We focus on the capacity of histone variants, chaperones,modifications, and heterochromatin factors to influence cell identity and its plasticity.Recent technological advances have provided tools to elucidate the underlyingchromatin dynamics for a better understanding of normal development andpathological conditions, with avenues for potential therapeutic application.

The genome of eukaryotic cells is organizedinto chromatin, a nuclear complex com-prising DNA, RNA, and associated proteins(1, 2). Chromatin organization displays hi-erarchical levels ranging from the basic

repeated unit, the nucleosome, to higher-levelstructures (Fig. 1). The nucleosome is composedof a core particle with ~147 base pairs of double-stranded DNA wrapped around histone pro-teins with linker DNA joining core nucleosomalunits. The chromatin filament further coils andcompacts DNA to reach higher-order states withinteracting chromatin loops and topologicallyassociating domains (TADs) (3). Histones comeas distinct variants that undergo posttranslationalmodification (PTM) to provide modularity within

core particles (1). Histone chaperones, chromatinremodelers, and histone- and DNA-modifying en-zymes, along with PTM readers, transcriptionfactors, and RNA, generate specialized genomicdomains for a versatile chromatin landscape.Centromeres, telomeres, and regulatory elementsdisplay unique nucleosome composition andstructure. Modulation at each level enableschromatin-based information to vary in orderto respond to different signals for numerous generegulatory functions (4) (Fig. 1). This defineschromatin plasticity as a means to generate adiversity of properties for each cell type duringdevelopment and also when cells face differentenvironmental factors, genotoxic insults, metabolicchanges, senescence, disease, and even death (5, 6).

Regulation of cell fate decisions and cell iden-tity can exploit chromatin, for example, by re-stricting access to a particular transcriptionfactor or by providing distinct marks that spe-cific proteins can recognize—proteins oftencalled “reader”—and can interpret in responseto signaling (7, 8). Thus, chromatin organizationis intimately linked to varied states experiencedby any single cell in its lifetime, and manychromatin changes occur during embryonic de-velopment inmammals (6, 9), in embryonic stemcells (ESCs) transitioning to a differentiated statein vitro (10), during reprogramming of differ-entiated cells to form multi- or pluripotent celltypes (11), and in various diseases (12). With theadvent of single-cell approaches (13), we arebeginning to capture transient or specializedstates in individual cells. DNA methylationrevealed major changes [see (4, 9, 14, 15) forreviews]. Here, we highlight recent reportsthat identify chromatin factors in controllingcell fate and identity with a focus on histonevariants, PTMs, chaperones, and heterochromatinfactors in the context of organismdevelopment, invitro cell differentiation, cellular reprogramming,and disease.

Chromatin shapes cell fate and identityin normal development

During development, highly differentiated cells,the gametes, fuse to form a totipotent zygote.This single cell then undergoes rounds of di-vision and differentiation to give rise to everycell type in the adult organism, including ga-metes. Lineage-specific gene expression profilesare initiated by cell type–specific transcription

GENES IN DEVELOPMENT

Yadav et al., Science 361, 1332–1336 (2018) 28 September 2018 1 of 5

Institut Curie, 75248 Paris Cedex 05, France.*Corresponding author. Email: genevieve.almouzni@curie.fr

Nuclear position

Higher-orderchromatin

Structural RNA

Nucleosome

Histone tails

Histone variants

DNA

Nucleus

ADP + Pi ATP

PTM

PTMDNA modificationsHistone chaperonesHistone modifiersHistone readersRemodeling factors

I.II.III.IV.V.

I

II

III

IV

V

Fig. 1. Chromatin plasticity. The hierarchy of chromatin organization in an interphase nucleus is shown along with factors acting at each level. Arraysof nucleosomes fold into higher-order chromatin structures, and noncoding RNA participates in local organization. Inset (right): The basic repeatingunit of chromatin, the nucleosome, comprises double-stranded DNA wrapped around an octamer consisting of a (H3-H4)2 tetramer flanked by twoH2A-H2B dimers. Variations of this basic module by dynamic combinations include the choice of histone variants, modifications of DNA bases, andreversible posttranslational modifications (PTM) of histone tails, enabling chromatin plasticity.A

DAPTED

BYKELLIEHOLO

SKI/SCIENCE,W

ITH

PERMISSIO

N,FR

OM

PROBSTETAL.

(2)

on January 6, 2021

http://science.sciencemag.org/

Dow

nloaded from

factors and controlled by signal transductionpathways. Acting in concert, chromatin factorscontribute to the chromatin landscape duringstages of cellular differentiation and overallorganism development. This is illustrated inparticular with histone chaperones and theirhistone variants that perform critical roles indevelopment (6). Here, we compile recent re-ports placing them within the developmentcycle of an organism. We highlight the mostdrastic changes during gametogenesis and earlyzygotic development for reprogramming (Fig. 2),with a focus on how heterochromatin can re-strict cell fate.

Gametogenesis

In mammals, genome compaction in spermato-genesis involves major histone reshuffling. Aspermatid-specific histone H2A variant, H2A.L.2, is required for the acquisition of nucleo-protamines and genome compaction in maturespermatozoa (16) (Fig. 2). During compaction,it is necessary to mark chromatin at specificgenes required for embryonic development. Inzebrafish, specialized “placeholder” nucleosomesconstitute a bookmarking mechanism to preventDNA methylation–mediated repression at house-keeping and early embryonic transcription fac-tor genes. They contain a special H2A variant,H2A.Z(FV), that co-occurs with the methylatedhistone H3 Lys4 (H3K4me1) mark in transcrip-tionally silent gamete and embryonic stages ofzebrafish development at key genomic regionsin order to ensure a supply of housekeepinggene products and transcription factors (17).Meanwhile, during oogenesis, certain histonePTMs differentiate active from inactive genomicregions. The trimethylated histone H3 Lys4

(H3K4me3) mark generally correlates withactive promoters but also occurs at a lesserdegree at nonactive regions. Overcoming thelimited amounts of mammalian genetic materialavailable from eggs and embryos, two recentstudies used low-input chromatin immuno-precipitation sequencing (ChIP-seq) to probeH3K4me3 levels during oogenesis (18, 19).Whereas only active promoters in nondividingoocytes showed H3K4me3, this PTM accu-mulated further as oogenesis progressed in atranscription-independent manner involvingthe MLL2 activity (18) (ncH3K4me3; Fig. 2).This noncanonical transcription-independentH3K4me3 marked intergenic regions, putativeenhancers, and trimethylated histone H3 Lys27

(H3K27me3)–silent promoters. Moreover, thenoncanonical H3K4me3 distributed over broadregions correlating with partially methylatedDNA domains on maternal genomes in matureoocytes. The presence of these noncanonicalH3K4me3 domains on the maternal allele inzygotes and two-cell embryos suggests inheri-tance from oocytes (19), a feature distinctfrom somatic cells and ESCs. Thus, peculiarinterplay between histone variants and keyhistone PTM shows remarkable dynamism asa marking system to prepare for subsequentdevelopment.

Zygotic development and cell trajectoriesAfter fertilization, development starts based onmaternally inherited proteins andRNAs from theegg cytoplasm. A crucial reprogramming of pa-rental epigenomes occurs to reach zygotic totip-otency. This transition involves the histone H3variant H3.3 and its associated chaperones, HIRAand DAXX, important both for meiotic segrega-tion and fertility in mammals (6) (Fig. 2). Aftermaternal-to-zygotic transition (MZT) and clear-ance of maternal products, zygotic genome ac-tivation (ZGA) is a time of extensive chromatinchanges (14). It takes place around the late two-cell stage in mice and four- to eight-cell stagesin human embryos. Recently, DNase I hyper-sensitivity (20) and scCOOL-seq (single-cell chro-matin overall omics-scale landscape sequencing)experiments (21) showed a gradual reestablish-ment of chromatin accessibility in human em-bryos (Fig. 2). High-throughput ATAC-seq (assayfor transposase-accessible chromatin) in humanpreimplantation embryos captured accessiblechromatin regions existing prior to ZGA, es-pecially at CpG-rich regions, several of thembecoming inaccessible after ZGA in a transcription-dependent manner (22). Before gastrulation, spa-tial heterogeneity of regulatory genomic regionscorrelates with future cell fate. In flies, single-cell ATAC-seq studies at different developmen-tal stages showed the dynamics of chromatinaccessibility during lineage commitment (23),demonstrating the temporal placement of cellsalong differentiation trajectories. During mid-

and late embryonic stages, tissue-specific signa-tures of chromatin accessibility emerge, althoughindividual cells still display features reminiscentof their original germ layer. The histone chaper-one CAF-1 (specifically, the large subunit p150),which incorporates replicative histone variantH3.1 necessary for cell division, is crucial forpreimplantation development (1, 2, 6) (Fig. 2).ZGA uses several barriers against precocious

activation of lineage-specific genes in early em-bryogenesis. These include active and repressivehistone PTMs. During ZGA in mice, repro-gramming of the noncanonical histone markH3K4me3 is observed. H3K4me3 inheritedin preimplantation embryos gets removed bythe lysine demethylases KDM5A and KDM5B(Fig. 2) to constrain this mark to transcriptionstart sites (TSS) in the late two-cell embryos atthe onset of zygotic transcription (24). Thus, incontrast to oocytes with broad domains, H3K4me3shows sharp, more confined peaks in late-stageembryos. Hence, a PTM associated with activelytranscribed and poised gene promoters is highlyplastic as embryos develop. Interestingly, theH3K27me3 mark associated with gene repres-sion imposed by Polycomb complexes showsdistinct dynamics. In Drosophila embryos, thematernal contribution of H3K27me3 counter-acts premature untimely accumulation of theactive H3K27ac mark at regulatory regions(25). Indeed, loss of the maternally inheritedH3K27me3 mark leads to embryonic lethalitythat cannot be circumvented by reestablishment

Yadav et al., Science 361, 1332–1336 (2018) 28 September 2018 2 of 5

Loss Mix Gain

RegenerationTissue maintenance

Adult organism

Cell lineagecommitment

Blastocyst

Pre-implantationdevelopment

OogenesisSuv4-20h1/h2/H4K20me3

Gradual chromatinaccessibility re-establishmentfollowing ZGA

Slow reappearanceof TADs

FertilizationSpermatogenesis

HIRA/H3.3H2A.L.2

KDM5A/KDM5B

CAF-1/H3.1H3.3

Setdb1/H3K9me3MLL2/ncH3K4me3

ncH3K4me3HIRA/H3.3

Fig. 2. Histone variants and modifications involved during the development cycle. Histonevariants and their chaperones, histone modifiers and posttranslational modifications (PTMs), andheterochromatin factors are used during various stages of mouse development. The dynamicchanges in the developmental cycle follow distinct steps: first an erasure or loss of parental marksduring gametogenesis, followed by the mix of marks after fertilization to reach totipotency, andfinally a progressive gain of specific chromatin marks and higher organization in line with thediversity of cell types forming the adult organism.

on January 6, 2021

http://science.sciencemag.org/

Dow

nloaded from

of the PTM at a later zygotic stage (25). Sim-ilarly, a recent study in mice found that oocyte-acquired H3K27me3 patterns are transmitted tothe zygote and involved in a novel form of DNAmethylation–independent genomic imprinting ofallelic loci in early embryos (26). Comparison ofH3K4me3 and H3K27me3 dynamics by small-scale ChIP-seq revealed that whereas the activemark is rapidly reestablished, H3K27me3 isslower in preimplantation embryos in mouse,Xenopus, and zebrafish (27).

Heterochromatin and cellfate restriction

Constitutive heterochromatin at pericentromericregions is commonly associated with trimethyl-ated histone H3 Lys9 (H3K9me3) incells (2, 28), a mark that acts as a keychromatin barrier to cell fate changes.The genome-wide distribution in mousegametes and early embryos (29) shows adynamic distribution of H3K9me3 at pro-moters and long terminal repeats (LTRs).After fertilization, both parental genomesshowmassive H3K9me3 reprogrammingand reestablishment, although the dis-crepancy in parental H3K9me3 signalslasts until the blastocyst stage and is notfully recovered. The large subunit of his-tone chaperone CAF-1 (mouse Chaf1a)is responsible for establishing H3K9me3on LTRs and their eventual silencing(29, 30). The observation of lineage-specific H3K9me3 raised interest in ex-ploring roles for heterochromatin inregulating cell fate commitment. Lossof Setdb1 (H3K9 methyltransferase) ingrowing oocytes leads to meiotic defectsand down-regulation of retrotransposonelements (31), and Setdb1 maternally de-ficient embryos arrest at preimplantation as aresult of cell cycle progression and chromosomesegregation defects (Fig. 2). The heterochromatinmark trimethylated histone 4 Lys20 (H4K20me3)is undetectable in mouse preimplantation em-bryos, and ectopic establishment of this mark byexpression of Suv4-20h1/h2 hinders development(Fig. 2), likely by altering S-phase progression inthis developmental context (32). How thesemodi-fications interconnect with H3K27me3 will beimportant to consider.As seen with H3K9me3 marks, after fertil-

ization both parental genomes show remarkableloss of 3D nuclear structure in a low-input Hi-Cstudy (33). The higher-order states, as reflectedwith interacting chromatin loops and definedtopologically associating domains (TADs), arethus lost. TAD boundaries and differential ge-nomic compartments arise only gradually inthe zygote, and a full restoration of the overallhigher-order architecture involves a long mat-uration process (3) (Fig. 2).Together, these recent discoveries highlight

critical chromatin dynamics during develop-ment and reproduction. Gametogenesis anddeveloping embryos in model organisms teachus how the chromatin machinery contributes

to fine-tuning of cell fate commitment. Thesemechanisms may also be reused during adultlife in regenerating tissues and potentially ex-ploited for therapeutic purposes in regenerativemedicine.

Lessons from cellular models: Studyingdevelopment in vitro

Cell culture of pluripotent ESCs (9) and 3D cul-ture models have proven extremely useful forexperimental manipulation of somatic andgermline stem cells and organoids (34). Recentfindings show that ground-state (derived usingthe so-called “2i” combination of GSK3 andMEKinhibitors), serum-grown, or “primed” mouseESCs (mESCs) and human ESCs exhibit features

of accessible chromatin in comparison withsomatic cells, although the features of chromatinare less distinct than in earlier preimplantationstages (35). Recently, mESC lines with taggedH3.3 permitted the tracking of H3.3 dynamicsbefore and after ESC differentiation (36, 37).Notably, in ESCs, a hyperdynamic (–1 position)H3.3 nucleosome marks gene promoters; upondifferentiation, this nucleosome shifts down-stream (to the +1 position) (36). These discretedynamics in histone variant positioning suggestthat fine-tuning at this level can regulate cellfate determination.The lifetime of a particular histone variant

is also a hallmark of stem cells, as shown in flyintestinal adult stem cells (ISCs). Notably, inISCs, the specific centromeric variant CENP-A is retained for weeks in the self-renewingpopulation—a mark of stemness (38). A long-lived form of CENP-A is thus characteristicof these populations of cells. In contrast, whenthese cells differentiate, in the daughter cells,the differentiating cell receives new CENP-Awith the help of the fly version of the mam-malian HJURP chaperone responsible forde novo CENP-A deposition, while the newdaughter stem cell retains the parental CENP-

A. This asymmetric distribution of the parentalCENP-A follows the fate of the stem cell. Thesereports provide attractive cellular models totrack cell fate changes and further probe therole of chromatin organization and dynamicsof H3 variants.Cellular models have also illuminated the

importance of heterochromatin in the genome.HP1 (heterochromatin protein 1)/Suv39h1 (his-tone methyltransferase) recruitment to activepromoters leads to reversible gene silencingin mESCs by establishing heterochromatin, asshown in experiments using FIRE-Cas9 (Fkbp/Frbinducible recruitment for epigenome editing byCas9) (39). Recent work in mESCs uncoveredan unusual form of repression involving HP1

together with ADNP (activity-dependentneuroprotective protein) and CHD4 (chro-matin remodeler) in a complex calledChAHP (40). ChAHP-mediated repressionacts locally and does not rely on H3K9me3-modified nucleosomes. Ablation of thiscomplex led to spontaneous differenti-ation along with precocious expressionof lineage-specific genes (40).Bivalent promoters are defined by the

presence of a nucleosome combiningboth an active mark (H3K4me3) anda repressive mark (H3K27me3) on thesame particle and thus poised to eitherbecome activated or kept repressed. Theyare more prevalent in cultured mESCsthan in mouse early embryos and pro-vide an entry point to explore how theirchromatin modulation contributes totranscriptional output. Activation ofbivalent genes occurs within minutesat target loci in mESCs when target-ing chromatin remodeling via mSWI/SNF(BAF) complexes using the FIRE-

Cas9 method to oppose the activity of Polycombcomplexes (39). Conversely, the prevalence ofPolycomb-mediated H3K27me3 at these pro-moters maintains them in a silent state. In-triguingly, H3K27 inheritance in mESCs maynot be only self-sustained, as initially proposed,because these patterns can be established de novo(41). This is in contrast to germline-inheritedPolycomb memory in flies and mice, as dis-cussed above (25, 26). Hence, the maternallytransmitted H3K27me3 that controls lineage-specific genes in vivo is not retained in themESCs.In common laboratory ESC cultures, most

cells are pluripotent, with infrequent two-cell–like cells exhibiting characteristics of totipotencywith increased plasticity. Quantitative polymer-ase chain reaction–based microfluidics single-cellexpression profiling characterized these two-cell–like cells, and a small interfering RNA–basedscreening revealed key chromatin factors, includ-ing a noncanonical Polycomb PRC1 complex(PRC1.6) and the EP400-TIP60 complex (42).Higher-order chromatin also undergoes dynamicchanges during differentiation of stem cells, asshown by high-resolution ultradeep Hi-C map-ping of the distinct signature in mESCs and

Yadav et al., Science 361, 1332–1336 (2018) 28 September 2018 3 of 5

Cell potency

Transcription factors?

CAF-1/H3.1Suv39h1Setdb1

HP1H3K9me3

Fig. 3. CAF-1 and heterochromatin as controllers of cellplasticity. A schematic model highlights the role of the histonechaperone CAF-1, the replicative histone H3 variant H3.1, andthe presence of the H3K9me3 mark typical of hetero-chromatin. Chromatin assembled using the replicative histonevariant, along with imposing the H3K9me3 mark, provides abarrier to stemness engaging cells in nonreversible cell fates.

GENES IN DEVELOPMENT on January 6, 2021

http://science.sciencemag.org/

Dow

nloaded from

neural progenitor cells where distal gene bodiesof active genes interact extensively (43). Duringneural differentiation, these preexisting long-range contacts between active TADs weakenwhile those between inactive regions becomestronger. Cell type–specific enhancer-promotercontacts are formed in parallel to the expressionof differentiation genes. Studies in ESCs havethus revealed unique roles of histone modifiers,variants, and chaperones in maintenance and/orchanges in cellular identity that could also proveimportant for reprogramming.

Chromatin plasticity in cellreprogramming and deregulationin pathologies

Manipulation in vitro affords the exciting pos-sibility of reverting unipotent differentiated cellsback to a pluripotent stem cell–like state, aprocess called reprogramming (11), as in thecase of induced pluripotent stem cells (iPSCs)derived directly from skin cells with a limitedset of transcription factors (44). However, thereprogramming efficiency remained limited,leading to a search for additional chromatinplayers involved in maintenance of somaticcell fate. The histone chaperone CAF-1, alongwith Setdb1, proved important in maintainingsomatic cell identity (45). Depletion of CAF-1augments the reprogramming efficiency of mouseembryonic fibroblasts (MEFs) (45). Interestingly,down-regulation of CAF-1(p150) in ESC leads toincreased induction of 2C-like cells with greaterpotency than the ESC (30). Notably, in additionto in vitro reprogramming, natural reprogram-ming also occurs in intestine regeneration andskin renewal of the adult organism. This is alsoexemplified by the immune response, which un-derscores the paradigm of chromatin plasticityin differentiated cells. Using single-cell RNA se-quencing, a recent study found that CD8+ T cellslacking Suv39h1 have enhanced long-term mem-ory and improved reprogramming capacity (46).The stability of the commitment into T helper 2(TH2) lineage from CD4+ T cells is maintained bythe SUV39H1-H3K9me3-HP1a pathway (46). Itis remarkable that in distinct contexts regardingthe degree of cell potency, both CAF-1 and theH3K9me3-heterochromatin pathways (i.e., Setdb1,Suv39h1, HP1a) restrict acquisition of increasedpotency and/or remodeling capacity (Fig. 3).Given the interactions and colocalization of CAF-1with HP1 domains during S phase (47) (Fig. 4),whether CAF-1 and H3K9me3-heterochromatinpathways act independently or in concert willneed further investigation. Furthermore, howthese chromatin modulations connect with thefunction of specific transcription factors andchanges in the cell cycle remains to be estab-lished. Nonetheless, this provides an exampleof different, overlapping chromatin layers in-fluencing cell fate decisions, which should beexplored for regeneration of cells in the adultorganism.Deregulation during normal aging and inmany

disease states represent natural in vivo cases ofunscheduled chromatin alterations and un-

desirable somatic cell fate changes. This isexemplified in aging and neurodegenerativediseases (48). During advanced age-relatedmacular degeneration (AMD), a major causeof vision loss in the elderly, chromatin acces-sibility (as determined by ATAC-seq) decreasesglobally in retinal pigmented epithelium (49).Cancer, where pathological mechanisms likelyhijack existing chromatin plasticity to cause dis-ease, further underlines the role of chromatin.Consider p53-deficient tumors that show a de-pendence on high levels of HJURP, the CENP-Achaperone, thereby suggesting that centromericchromatin integrity is involved in tumor main-tenance (50). HJURP is also an independentprognostic marker of luminal A breast carcinoma(51). These data link together chromosomal ar-chitecture and centromere function in cell fatemaintenance. In addition to the centromerichistone variant, other histone H3 variants (H3.1and H3.3) and histone chaperones have beenimplicated in malignancies. Widespread effortsare under way to examine the molecular eti-ology of oncohistones carrying point mutationsin histone H3 Lys27, Gly34, and Lys36 linked todistinct cancer types, respectively (52, 53). Inthese situations too, histone variant choice,histone chaperone, histone modifications, andheterochromatin are simultaneously involvedin the dysregulation of cell identity.A deeper understanding of the chromatin

plasticity that wires these cell fate decisions isnow guiding precision medicine and targetedtherapeutics in a move toward cell precisionmedicine. Small-molecule inhibitors againstEZH2 are being widely tested in trials alongwith other Polycomb subunit and BET bromo-domain (chromatin reader domains that recog-nize acetylated histones) inhibitors that haveshown therapeutic potential in diffuse intrin-sic pontine glioma (DIPG) (53, 54). Trying tobetter target the cells that are most suscepti-ble to the intervention at the chromatin levelwill be crucial. Moving forward, the ability toobtain patient-derived iPSCs and organoids tocarry out transdifferentiation offers new open-ings to examine and address aging as well as to

treat diseases such as cancer and degenerativemaladies.

Conclusion

Research in developmental and stem cell biol-ogy has become increasingly enmeshedwith thestudy of chromatin-based regulatorymechanisms.Although cell identity and chromatin organi-zation are intimately linked, understandingwhether chromatin plasticity is the cause or con-sequence of cell fate changes requires furtherinvestigation with dedicatedmodel systems. Withthe help of multidisciplinary approaches look-ing at single-cell dynamics with high-resolutionimaging in combination with high-throughput“omics” methods, there is now hope to answerquestions about cellular heterogeneity and cellidentity specificationwith unprecedented preci-sion (55, 56). In regenerative medicine anddisease treatment, targeting chromatin factorsrepresents a promising avenue. Currently, im-munotherapy and anticancer compounds com-bined with actionable chromatin targets are atthe forefront of medicine. Multidisciplinary ap-proaches will be instrumental to gain a compre-hensive view of chromatin plasticity that mayyield an understanding of how to switch betweenspecific cellular states at will for therapeuticapplication.

REFERENCES AND NOTES

1. D. Sitbon, K. Podsypanina, T. Yadav, G. Almouzni, Cold SpringHarb. Symp. Quant. Biol. 82, 1–14 (2017).

2. A. V. Probst, E. Dunleavy, G. Almouzni, Nat. Rev. Mol. Cell Biol.10, 192–206 (2009).

3. E. E. M. Furlong, M. Levine, Science 361, 1341–1345 (2018).4. A. Bird, Nature 447, 396–398 (2007).5. A. Groth, W. Rocha, A. Verreault, G. Almouzni, Cell 128,

721–733 (2007).6. D. Filipescu, S. Müller, G. Almouzni, Annu. Rev. Cell Dev. Biol.

30, 615–646 (2014).7. R. C. Adam, E. Fuchs, Trends Genet. 32, 89–100 (2016).8. A. Burton, M. E. Torres-Padilla, Nat. Rev. Mol. Cell Biol. 15,

723–734 (2014).9. Y. Atlasi, H. G. Stunnenberg, Nat. Rev. Genet. 18, 643–658

(2017).10. E. Meshorer, T. Misteli, Nat. Rev. Mol. Cell Biol. 7, 540–546

(2006).11. K. Hochedlinger, R. Jaenisch, Cold Spring Harb. Perspect. Biol.

7, a019448 (2015).

Yadav et al., Science 361, 1332–1336 (2018) 28 September 2018 4 of 5

CAF-1(p150) DNA synthesis DAPI

5 µm

MergeHP1α

Fig. 4. CAF-1 and heterochromatin marks within the cell. During late S phase at sites of5-bromo-2′-deoxyuridine incorporation that reveal replication sites, CAF-1 closely localizes in fociwith HP1a. A mouse embryonic fibroblast shows localization of the large subunit of CAF-1 (p150),HP1a, DNA synthesis, and DNA. We visualized p150 and HP1a by immunofluorescence staining,DNA synthesis by immunodetection of BrdU incorporation, and DNA by 4′,6-diamidino-2-phenylindole(DAPI) staining as described in (47). A merge of the staining corresponding to detection of thelarge subunit of CAF-1 (p150) and HP1a is shown. The arrowheads point to (pericentric)heterochromatin domains.

on January 6, 2021

http://science.sciencemag.org/

Dow

nloaded from

12. A. C. Mirabella, B. M. Foster, T. Bartke, Chromosoma 125,75–93 (2016).

13. G. Kelsey, O. Stegle, W. Reik, Science 358, 69–75(2017).

14. M. A. Eckersley-Maslin, C. Alda-Catalinas, W. Reik, Nat. Rev.Mol. Cell Biol. 19, 436–450 (2018).

15. C. Luo, P. Hajkova, J. R. Ecker, Science 361, 1336–1340(2018).

16. S. Barral et al., Mol. Cell 66, 89–101.e8 (2017).17. P. J. Murphy, S. F. Wu, C. R. James, C. L. Wike, B. R. Cairns,

Cell 172, 993–1006.e13 (2018).18. C. W. Hanna et al., Nat. Struct. Mol. Biol. 25, 73–82

(2018).19. B. Zhang et al., Nature 537, 553–557 (2016).20. L. Gao et al., Cell 173, 248–259.e15 (2018).21. L. Li et al., Nat. Cell Biol. 20, 847–858 (2018).22. J. Wu et al., Nature 557, 256–260 (2018).23. D. A. Cusanovich et al., Nature 555, 538–542 (2018).24. J. A. Dahl et al., Nature 537, 548–552 (2016).25. F. Zenk et al., Science 357, 212–216 (2017).26. A. Inoue, L. Jiang, F. Lu, T. Suzuki, Y. Zhang, Nature 547,

419–424 (2017).27. X. Liu et al., Nature 537, 558–562 (2016).28. A. H. Peters et al., Cell 107, 323–337 (2001).29. C. Wang et al., Nat. Cell Biol. 20, 620–631 (2018).30. T. Ishiuchi et al., Nat. Struct. Mol. Biol. 22, 662–671

(2015).

31. A. Eymery, Z. Liu, E. A. Ozonov, M. B. Stadler, A. H. Peters,Development 143, 2767–2779 (2016).

32. A. Eid, D. Rodriguez-Terrones, A. Burton, M. E. Torres-Padilla,Genes Dev. 30, 2513–2526 (2016).

33. Z. Du et al., Nature 547, 232–235 (2017).34. J. Drost, H. Clevers, Nat. Rev. Cancer 18, 407–418 (2018).35. J. Wu et al., Nature 534, 652–657 (2016).36. S. Schlesinger et al., Nucleic Acids Res. 45, 12181–12194

(2017).37. A. M. Deaton et al., eLife 5, e15316 (2016).38. A. García Del Arco, B. A. Edgar, S. Erhardt, Cell Rep. 22,

1982–1993 (2018).39. S. M. G. Braun et al., Nat. Commun. 8, 560 (2017).40. V. Ostapcuk et al., Nature 557, 739–743 (2018).41. J. W. Højfeldt et al., Nat. Struct. Mol. Biol. 25, 225–232

(2018).42. D. Rodriguez-Terrones et al., Nat. Genet. 50, 106–119

(2018).43. B. Bonev et al., Cell 171, 557–572.e24 (2017).44. K. Takahashi, S. Yamanaka, Cell 126, 663–676 (2006).45. S. Cheloufi et al., Nature 528, 218–224 (2015).46. L. Pace et al., Science 359, 177–186 (2018).47. J.-P. Quivy et al., EMBO J. 23, 3516–3526 (2004).48. A. Berson, R. Nativio, S. L. Berger, N. M. Bonini, Trends

Neurosci. 41, 587–598 (2018).49. J. Wang et al., Nat. Commun. 9, 1364 (2018).50. D. Filipescu et al., Genes Dev. 31, 463–480 (2017).

51. R. Montes de Oca et al., Mol. Oncol. 9, 657–674 (2015).52. K. Funato, V. Tabar, Annu. Rev. Cancer Biol. 2, 337–351

(2018).53. F. Mohammad, K. Helin, Genes Dev. 31, 2313–2324

(2017).54. D. Morel, G. Almouzni, J. C. Soria, S. Postel-Vinay, Ann. Oncol.

28, 254–269 (2017).55. S. J. Clark et al., Nat. Commun. 9, 781 (2018).56. R. M. Harland, Science 360, 967–968 (2018).

ACKNOWLEDGMENTS

We thank our colleagues in the team for critical reading, andthe many inputs for our thinking in the Labex DEEP. Weapologize to colleagues whose important work could not becited here. Because of space constraints and a focus onrecent reports, we used reviews to provide backgroundand reference to the primary research papers. Funding: Oursupport comes from la Ligue Nationale contre le Cancer(Equipe labelisée Ligue), ANR-11-LABX-0044_DEEPand ANR-10-IDEX-0001-02 PSL, ANR-12-BSV5-0022-02“CHAPINHIB,” ANR-14-CE16-0009 “Epicure,” ANR-14-CE10-0013“CELLECTCHIP,” EU project 678563 “EPOCH28,” ERC-2015-ADG-694694 “ChromADICT,” ANR-16-CE15-0018 “CHRODYT,”ANR-16-CE12-0024 “CHIFT,” and ANR-16-CE11-0028 “REPLICAF.”Competing interests: None declared.

10.1126/science.aat8950

Yadav et al., Science 361, 1332–1336 (2018) 28 September 2018 5 of 5

GENES IN DEVELOPMENT on January 6, 2021

http://science.sciencemag.org/

Dow

nloaded from

Chromatin plasticity: A versatile landscape that underlies cell fate and identityTejas Yadav, Jean-Pierre Quivy and Geneviève Almouzni

DOI: 10.1126/science.aat8950 (6409), 1332-1336.361Science 

ARTICLE TOOLS http://science.sciencemag.org/content/361/6409/1332

CONTENTRELATED

http://science.sciencemag.org/content/sci/361/6409/1346.fullhttp://science.sciencemag.org/content/sci/361/6409/1341.fullhttp://science.sciencemag.org/content/sci/361/6409/1336.fullhttp://science.sciencemag.org/content/sci/361/6409/1330.full

REFERENCES

http://science.sciencemag.org/content/361/6409/1332#BIBLThis article cites 56 articles, 13 of which you can access for free

PERMISSIONS http://www.sciencemag.org/help/reprints-and-permissions

Terms of ServiceUse of this article is subject to the

is a registered trademark of AAAS.ScienceScience, 1200 New York Avenue NW, Washington, DC 20005. The title (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement ofScience

Copyright © 2018, American Association for the Advancement of Science

on January 6, 2021

http://science.sciencemag.org/

Dow

nloaded from