MEDICINAL CHEMISTRY

Click chemistry enables preclinicalevaluation of targetedepigenetic therapiesDean S. Tyler,1,2* Johanna Vappiani,3* Tatiana Cañeque,4,5,6 Enid Y. N. Lam,1,2

Aoife Ward,3 Omer Gilan,1,2 Yih-Chih Chan,1 Antje Hienzsch,4,5,6 Anna Rutkowska,3

Thilo Werner,3 Anne J. Wagner,3 Dave Lugo,7 Richard Gregory,7

Cesar Ramirez Molina,7 Neil Garton,7 Christopher R. Wellaway,7 Susan Jackson,1

Laura MacPherson,1,2 Margarida Figueiredo,1 Sabine Stolzenburg,1 Charles C. Bell,1,2

Colin House,1 Sarah-Jane Dawson,1,2,8 Edwin D. Hawkins,9 Gerard Drewes,3

Rab K. Prinjha,7 Raphaël Rodriguez,4,5,6 Paola Grandi,3†‡ Mark A. Dawson1,2,8,10†‡

The success of new therapies hinges on our ability to understand their molecular andcellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to clickchemistry and can be used as molecular probes in vitro and in vivo. We used clickproteomics and click sequencing to explore the gene regulatory function of BRD4(bromodomain containing protein 4) and the transcriptional changes induced by BETinhibitors. In our studies of mouse models of acute leukemia, we used high-resolutionmicroscopy and flow cytometry to highlight the heterogeneity of drug activity within tumorcells located in different tissue compartments. We also demonstrate the differentialdistribution and effects of BET inhibitors in normal and malignant cells in vivo. This studyprovides a potential framework for the preclinical assessment of a wide range of drugs.

Investment and progress in medicinal chem-istry has led to the promise of personalizedmedicinewith targeted therapies (1). Althoughthese efforts have seen several novel thera-peutic classes emerge and show early prom-

ise in the research laboratory, very few of thesedrugs ultimately make a sustained transition intothe clinical arena (1). Underpinning this failurein the clinical domain is a lack of knowledge ofthe molecular and cellular effects of these thera-pies. When assessing a new small molecule, it isdesirable to visualize the cellular localization ofthe compound (2–4); identify the protein targetsthat the molecule engages within a cell; and, fordrugs that target nuclear proteins, understandwhere in the genome the drug is located. Sim-ilarly, when assessing cancer therapies in animalmodels, it would be advantageous to assess dif-

ferential effects of the drug in cancer cells andnormal cells within different organs involvedwith the disease.BET bromodomain inhibitors are drugs that

target chromatin-associated proteins. Althoughthey have shown promise in both malignant andnonmalignant conditions (5), the mechanismsthat govern sensitivity or resistance to thesedrugs are poorly understood. We sought to mod-ify different BET inhibitors so that they couldbe used as molecular probes in a manner sim-ilar to the way in which antibodies are used incell and molecular biology research. We andothers have previously used small molecules, in-cluding BET inhibitors, as an affinity matrix forchemoproteomics (6, 7) and chemical sequenc-ing (Chem-seq) (4, 8). These approaches, whichincluded coupling of the small molecule to a bio-tinylated polyethylene glycol, can compromisecellular uptake and intracellular drug-target in-teractions, thus limiting the ability to accuratelydelineate mechanisms of action (fig. S1). To pre-serve the functional integrity of the small mole-cules, we repurposed the biologically active BETinhibitors to contain distinct chemically reactivemoieties amenable to bioorthogonal chemical li-gation by click chemistry. This approach allowsfluorochromes and/or affinity tags to react withthe functionalized drugs in a cellular context(Fig. 1A). Click reactions used in biological ap-plications include the copper-catalyzed and theinverse electron-demand Diels–Alder cycload-ditions involving azide-alkyne and tetrazine-trans-cyclooctene partners, respectively (9–11).Thus, we synthesized derivatives of the BET in-hibitors JQ1 and IBET-762—namely, JQ1–propargyl

amide (JQ1–PA), JQ1–trans-cyclooctene (JQ1–TCO),and IBET-762–TCO, along with a biotinylated de-rivative of JQ1 (JQ1–BTN)—for comparison (Fig.1A and materials and methods).We compared the effects of the clickable com-

pounds with those of the parental compounds byassessing in vitro cell proliferation, apoptosis, andcell cycle progression (Fig. 1, B to D, and fig. S1), asthese are themajor cellular phenotypes altered byBET inhibitors (7, 12). In each of these assays, theclickable derivatives phenocopied their unmod-ified counterparts. The clickable inhibitors alsoengaged their bromodomain targets and dis-placed the BET proteins from chromatin, asassessed by chromatin immunoprecipitation(ChIP)–quantitative polymerase chain reaction(qPCR) (Fig. 1E and fig. S1C). In addition, thegene expression programs altered by the click-able inhibitors were virtually identical to thoseof the parental drugs (Fig. 1F and fig. S1, D andE), thus confirming that the moderate struc-tural alterations we introduced did not affectthe functional integrity of the BET inhibitors.We next explored the molecular activity of the

clickable compounds by localizing their chroma-tin occupancy (Fig. 2A). We used a method wetermed “click sequencing” (click-seq), whichallowed us to identify specific drug–chromatintarget interactions in different cell lines (Fig. 2,B and C, and fig. S2). Although BRD4 occupancyand the influence of BET inhibitors on gene reg-ulation have been studied extensively, it is un-clear why only a subset of putative gene targetsare down-regulated upon BET bromodomain in-hibition.We found that upon BET bromodomaininhibition, chromatin-bound BRD4 was moresubstantially displaced from enhancer elementscompared with the transcriptional start site (TSS)of actively transcribed genes (fig. S3A). Chromatinoccupancy of BRD4 around the TSS did not differbetween genes that are responsive and unrespon-sive to BET inhibitors (fig. S3B). As BRD4 can belocalized to cis-regulatory elements at chromatinvia its tandembromodomainsor inabromodomain-independent manner via interaction with otherchromatin-associated proteins (13), this resultprompted us to investigatewhether local drug con-centration within the transcriptional unit wouldbe a better indicator of BET inhibitor response.Using click-seq, we found that genes that are im-mediately down-regulated upon BET inhibitionhave a markedly higher chromatin occupancy ofthe drug across the transcription unit (Fig. 2D andfig. S3, B and C). Thus, by directly assessing thelevels of drug localized across the transcriptionalunit, we are able to identify the BET inhibitor–responsive genes by means of a single click-seqexperiment.Together, these findings suggesteddistinctmodes

of binding of BRD4 at the BET inhibitor–responsiveand –unresponsive genes. It has previously beenestablished that BRD4 associates with chromatinmost avidly by binding acetylated (ac) lysines (K),primarily K5ac and K8ac on the tail of histoneH4 (14, 15). Consistent with this, we observed in-creased levels of H4K5ac and H4K8ac spanningthe TSS of the down-regulated genes (fig. S3D).

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1Cancer Research Division, Peter MacCallum Cancer Centre,Melbourne, Victoria, Australia. 2Sir Peter MacCallumDepartment of Oncology, University of Melbourne,Melbourne, Victoria, Australia. 3Cellzome GmbH,GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.4Chemical Cell Biology Group, Institut Curie, Paris Scienceset Lettres Research University, 26 Rue d’Ulm, 75248 ParisCedex 05, France. 5CNRS UMR3666, 75005 Paris, France.6INSERM U1143, 75005 Paris, France. 7Epigenetics DiscoveryPerformance Unit, Immuno-Inflammation Therapy Area Unit,GlaxoSmithKline, Stevenage, UK. 8Centre for CancerResearch, University of Melbourne, Melbourne, Victoria,Australia. 9The Walter and Eliza Hall Institute of MedicalResearch, Parkville, Victoria, Australia. 10Department ofHaematology, Peter MacCallum Cancer Centre, Melbourne,Victoria, Australia.*These authors contributed equally to this work. †These authorscontributed equally to this work. ‡Corresponding author. Email:paola.x.grandi@gsk.com (P.G.); mark.dawson@petermac.org(M.A.D.)

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To explain the increased drug localization at thedown-regulated genes,wehypothesized that chro-matin binding at these sites is principally me-diated via the first bromodomain (BD1) of BRD4(16, 17), which would leave the second bromo-domain (BD2) free to engage and localize thedrug in click-seq studies. In line with this prem-ise, we found that a point mutation that com-promises the acetyl-lysine binding ability of BD1[Tyr97→Ala97 (Y97A)] was sufficient to impair thefunctional activity of BRD4 in acute myeloid leu-kemia (AML) cells. In contrast, functional im-pairment of BD2 (Y390A) was less deleterious(fig. S4). To demonstrate that the clickable com-pounds primarily localize at chromatin by bind-ing to BD2, we used the BD2-selective drug RVX-208 (18). Although RVX-208 did not displaceBRD4 from chromatin or result in functionalimpairment, the compound’s preferential oc-cupancy of BD2 selectively impaired the abilityof the clickable JQ1 to engage BRD4 at chro-matin (figs. S5 and S6). These findings demon-

strate that at the BET inhibitor–responsive genes,BRD4 is bound toH4K5ac andH4K8ac by its firstbromodomain, and these sites can be identi-fied with click-seq as the compound engages itssecond bromodomain. Binding of BRD4 at theunresponsive genes is not only bromodomainindependent but may occur in a manner thatprecludes access of the drug to either BD1 orBD2. These data also highlight the therapeuticpotential of domain-specific inhibitors targetedto BD1 of BRD4.Next we examined themodes of BRD4binding

at enhancer elements where BRD4 binding ismore broadly regulated by bromodomain inhibi-tion (fig. S3A). A direct comparison of JQ1 click-seq with BRD4 ChIP sequencing (ChIP-seq) datasuggested that relative to BRD4 binding, someenhancers had greater drug occupancy thanothers (Fig. 2E and fig. S3E). In contrast to theevents at the TSS, BRD4 was equally displacedfrom chromatin at regions with the highest andlowest drug occupancy, suggesting that at en-

hancers, BRD4 is localized to chromatin primar-ily in a bromodomain-dependent manner (fig.S3F). Enhancers with high drug occupancy con-tained high levels of acetylated histone H4 (fig.S3G) to which BD1 was bound; BD2 was free toengage the clickable compound (fig. S6). In com-parison, at regions of low drug occupancy, theinaccessibility of the drug at these sites suggestedthat either BD2 was also bound to an acetylatedlysine residue or was sterically hindered as a re-sult of interactions with a chromatin-associatedprotein. To further investigate themode of BRD4binding at the enhancer elements with low drugoccupancy, we performed transcription factorbinding site analyses, as BRD4 has recently beenshown to associate with transcription factors atchromatin (19, 20). These regions were enrichedfor binding sites of transcription factors C/EBPaand C/EBPb, which directly bind BRD4 (19) (fig.S3H). ChIP-seq analyses confirmed that C/EBPaand C/EBPb colocalized with BRD4 at chromatinand were flanked by acetylated histones (Fig. 2E).

Tyler et al., Science 356, 1397–1401 (2017) 30 June 2017 2 of 5

Fig. 1. Clickable compoundsphenocopy the parental com-pounds. (A) Molecularstructures of BET inhibitorsand clickable and biotinylatedsurrogates. (B) Proliferation ofMV4;11 cells after 72 hours oftreatment, comparing JQ1 ver-sus JQ1–PA. Mean ± SD (errorbars) (n = 3 biological repli-cates). IC50, median inhibitoryconcentration. (C) Apoptosisassessed by FACS (fluorescence-activated cell sorting) analysisafter 72 hours of incubation withdimethyl sulfoxide (DMSO), JQ1(1 mM), or JQ1–PA (1 mM). PI,propidium iodide. (D) Cell cycleprofile of MV4;11 cells after 48hours of treatment with DMSO,JQ1, JQ1–PA, or JQ1–TCO (allcompounds used at 500 nM).Mean ± SD (error bars) (n = 3).(E) qPCR analysis of BRD4 ChIPfrom MV4;11 cells treated withJQ1 (1 mM) compared with JQ1–PA (1 mM) or JQ1–TCO (1 mM),with primers against MYC. Mean± SD (error bars), representativegraph from three independentexperiments. (F) RNA sequenc-ing (RNA-seq) performed inMV4;11 cells treated with JQ1 orJQ1–PA compared with DMSOcontrol. Correlation of log2 foldchange of JQ1–PA with log2 foldchange of JQ1 is shown. Signifi-cantly up- and down-regulatedgenes are depicted in red andblue, respectively. LFC, log foldchange.

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An often unresolved mechanistic issue con-cerning preclinical assessment of distinct com-pounds used against the same protein targets iswhether their selectivity for the target and as-sociated protein complexes varies, thus confer-ring differential efficacy. To address this, weperformed quantitative click proteomics withIBET-151 and JQ1 and showed that these chem-ically distinct compounds associated with thesame intracellular protein complexes (Fig. 2Fand fig. S7), thereby explaining the identicalcellular and molecular activity of these com-pounds and why resistance to one chemical classconfers cross resistance (21).

We next assessed the clickable BET inhibitorsin cultured cells by immunofluorescence andflow cytometry (fig. S8). Using different click-able BET inhibitors, we demonstrated colocal-ization of the clickable drugs with their targetBRD4 in the nuclei of both hematopoietic andnonhematopoietic cells (Fig. 3, A and B, andfig. S8D). We also used flow cytometry to ac-curately quantify the intracellular amount ofclickable surrogate drugs (Fig. 3C) and showedthat we could easily identify the population ofcells exposed to the highest amount of drug inmixing experiments (fig. S8E). Furthermore,we also noted that intracellular levels of the drug

were not influenced by cell cycle progression orproliferative capacity (fig. S8C).An assumption sometimes made in preclinical

and clinical cancer studies is that drug distri-bution and efficacy are equal across differenttissues involved with the malignancy. Using thesame preclinical model in which the efficacy ofthe BET inhibitors in AMLwas established (7, 12)(Fig. 4A), we found that these drugs displayedmarked differences in tumor cell activity thatwere dependent on tumor location (fig. S9). Theseresults are consistent with the previous observa-tion that BET inhibitors rapidly clear AML cellscirculating in the peripheral blood or localizedwithin the spleen but not those within the bonemarrow (7). These findings are potentially clini-cally relevant, as they reflect features of tumorcell clearance observed in some patients enrolledon the ongoing clinical trials with BET inhibitors.To evaluate whether drug access correlated

with the observed tumor cell activity, we as-sessed the intracellular concentration of BETinhibitors withinAML cells localized in the spleencompared with those resident in the bone mar-row of animals dosed with a clickable BET in-hibitor. Using JQ1-TCO, which had a log P valuesimilar to that of JQ1 (fig. S9A), we found thatdrug levels and, consequently, repression of BRD4target genes were significantly higher within theAML cells contained in the spleen of the animals(Fig. 4B and fig. S9, C and E). To show that theclickable compounds accurately reflect the phar-macokinetic properties of the parent drug, weharvested hematopoietic cells from the spleenand bone marrow of mice dosed with JQ1 andanalyzed these samples by quantitative intra-cellular mass spectrometry. These data confirmedthat drug concentrations are significantly higherin the spleen compared with the bone marrow(fig. S9C). These findings may help to explainwhy, when exposed to sustained subtherapeuticlevels of BET inhibitors, leukemia stem cellsresident within the bone marrow become re-fractory to treatment (21). They also raise thepossibility that compounds with greater bonemarrow penetration may improve the efficacyof BET inhibitors.To further highlight the power of chemically

tagging functionally identical small moleculesand to address the important preclinical issue oftherapeutic window, we next quantitated in vivothe level of drug within normal and malignanthematopoietic cells within the same tissue (Fig.4C). We found that the relative levels of intracel-lular drug were greater in AML cells comparedwith normal hematopoietic cells. Consistent withthese data,we found that repression of gene targetsof BET inhibitors correlatedwith intracellular druglevels (fig. S9E). These findingsmay help to explainwhy marked cytopenias were not observed inhealthy animals treated at drug concentrationsthat had shown good therapeutic efficacy (7).Understanding drug distribution within the

architecture of a tissue represents an importantasset in evaluating new therapies. We thereforedeveloped the methodology to assess levels ofdrug at a cellular resolution within any tissue

Tyler et al., Science 356, 1397–1401 (2017) 30 June 2017 3 of 5

Fig. 2. Click chemistry reveals insights into the binding of BRD4 to chromatin. (A) Schematicillustration of click-seq and click-proteomics experiments with modified JQ1 and IBETmolecules.(B) Heat map of BRD4 ChIP-seq and JQ1–PA click-seq sequencing reads in the 5 kb around the TSS.JQ1 is included as a negative control. (C) Genome browser view of the MYC enhancer, comparingBRD4 ChIP-seq with click-seq using IBET-762–TCO and JQ1–TCO molecules, with competition fromunmodified IBET-151 and JQ1. (D) Genes down-regulated or up-regulated after BET inhibitortreatment for 6 hours, assessed for drug occupancy with JQ1-PA click-seq. RPM, reads per million.(E) Genome browser view of two genomic regions with low and high levels of JQ1–PA relative toBRD4 with C/EBPa and C/EBPb ChIP-seq. (F) Quantitative mass spectrometry of proteins from thelysate of K562 cells captured by click-probes (IBET-762–TCO and JQ1–TCO) in the presence orabsence of the respective competitor (IBET-151 and JQ1). Correlation of log2 fold change ofabundance of protein captured in the presence of inhibitor relative to vehicle. Circle size representsthe quantity of protein from the mass spectrometer.

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compartment (Fig. 4D). With this technology,one can evaluate drug distribution in variousniches, compartments, and cells of interest bycostaining cells with the appropriate immuno-phenotypic markers.The success of personalized medicine rests

on characterizing the mechanisms of action oftargeted therapies. We have established an ex-

perimental framework that allows clickable drugsurrogates to be used as versatilemolecular probes.These compounds can be used to examine the ben-efits and limitations of novel drugs at themolecularlevel. Moreover, these probes can be used in modelorganisms to critically evaluate efficacy, toxicity,and resistance. Together, this knowledge mayultimately improve clinical outcomes.

REFERENCES AND NOTES

1. M. Hay, D. W. Thomas, J. L. Craighead, C. Economides,J. Rosenthal, Nat. Biotechnol. 32, 40–51 (2014).

2. T. Cañeque et al., Nat. Chem. 7, 744–751 (2015).3. A. Rutkowska et al., ACS Chem. Biol. 11, 2541–2550

(2016).4. R. Rodriguez, K. M. Miller, Nat. Rev. Genet. 15, 783–796

(2014).5. M. A. Dawson, Science 355, 1147–1152 (2017).

Tyler et al., Science 356, 1397–1401 (2017) 30 June 2017 4 of 5

Fig. 3. Clickable compounds can be visualized and quantified in vitro. (A) Schematic illustration of the methodology for click fluorescence and flowcytometry. (B) Confocal microscopy of HeLa cells treated with IBET-762–TCO or JQ1–TCO. Nuclei were stained with 4′,6-diamidino-2-phenylindole(DAPI), drug was labeled with Cy5–tetrazine, and BRD4 was stained with an anti-BRD4 antibody. Scale bars, 20 mm. (C) MV4;11 cells treated with JQ1or increasing concentrations of JQ1–PA, followed by click labeling with 488–azide. Flow cytometry analysis is represented as a histogram.

Fig. 4. Preclinical assessment of clickable compounds in vivo.(A) Schematic illustration of the methodology to detect the clickablesmall molecules in vivo. (B) Flow cytometry analysis of Venus+ sortedcells from the bone marrow and spleen of a mouse treated with JQ1–TCOfor 3.5 hours. (C) Flow cytometry analysis of drug levels within normalhematopoietic cells (Venus–) and leukemia cells (Venus+). (D) Confocal

microscopy of mouse femur tissue treated with 100 mg/kg of JQ1–TCO.Leukemia cells (LC) are identified by Venus reporter. The high magnifica-tion of the merged image (at right) reveals the ability to discern individualleukemia cells containing drug in situ. Scale bars, 187 mm. All datademonstrated here are representative examples of experiments performedin biological duplicate.

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6. S. E. Ong et al., Proc. Natl. Acad. Sci. U.S.A. 106, 4617–4622(2009).

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4686–4687 (2003).12. J. Zuber et al., Nature 478, 524–528 (2011).13. J. Shi, C. R. Vakoc, Mol. Cell 54, 728–736 (2014).14. O. Gilan et al., Nat. Struct. Mol. Biol. 23, 673–681 (2016).15. G. LeRoy et al., Genome Biol. 13, R68 (2012).16. A. Dittmann et al., ACS Chem. Biol. 9, 495–502 (2014).17. M. G. Baud et al., Science 346, 638–641 (2014).18. S. Picaud et al., Proc. Natl. Acad. Sci. U.S.A. 110, 19754–19759

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ACKNOWLEDGMENTS

Work in the Dawson laboratory is supported by the National Healthand Medical Research Council of Australia (grants 1106444, 1085015,and 1106447 to M.A.D.). M.A.D. is currently supported by a SeniorLeukaemia Foundation Australia Fellowship and a VESKI InnovationFellowship. D.S.T. and O.G. are respectively supported by a Ph.D.scholarship and a postdoctoral fellowship from Leukaemia FoundationAustralia. E.Y.N.L. and L.M. are supported by fellowships from theVictoria Cancer Agency. Work performed at Cellzome was supported inpart by funding from the European Union (FP7 Project BLUEPRINT/282510). We thank V. Benes and the European Molecular BiologyLaboratory GeneCore facility for DNA sequencing. Research in theRodriguez laboratory is supported by the Emergence Ville de ParisProgram and funding from the European Research Council underthe European Union’s Horizon 2020 research and innovation

program (grant agreement 647973). Reagents JQ1-TCO, JQ1-PA,IBET762-TCO, and IBET151 and plasmids for BRD4 are availablefrom the corresponding authors under a material transferagreement with Institut Curie, GlaxoSmithKline, and PeterMacCallum Cancer Centre. GlaxoSmithKline holds patent WO2011054846 A1, which covers IBET151. The ChIP-seq, click-seq, andRNA-seq data are available from the National Center forBiotechnology Information Gene Expression Omnibus repositoryunder accession number GSE88751.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/356/6345/1397/suppl/DC1Materials and MethodsFigs. S1 to S9References (22–42)

17 October 2016; accepted 1 June 2017Published online 15 June 201710.1126/science.aal2066

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Click chemistry enables preclinical evaluation of targeted epigenetic therapies

Mark A. DawsonColin House, Sarah-Jane Dawson, Edwin D. Hawkins, Gerard Drewes, Rab K. Prinjha, Raphaël Rodriguez, Paola Grandi and Christopher R. Wellaway, Susan Jackson, Laura MacPherson, Margarida Figueiredo, Sabine Stolzenburg, Charles C. Bell,Anna Rutkowska, Thilo Werner, Anne J. Wagner, Dave Lugo, Richard Gregory, Cesar Ramirez Molina, Neil Garton, Dean S. Tyler, Johanna Vappiani, Tatiana Cañeque, Enid Y. N. Lam, Aoife Ward, Omer Gilan, Yih-Chih Chan, Antje Hienzsch,

originally published online June 15, 2017DOI: 10.1126/science.aal2066 (6345), 1397-1401.356Science 

, this issue p. 1397Sciencedrugs accumulate to different extents in the spleen and bone marrow, which are two tissue sources of leukemic cells.modes of binding at responsive and unresponsive genes. In a mouse leukemia model, the click-probes revealed that the expression. Clickable derivatives of the drugs localized within chromatin and showed that the drugs exhibit distinctstudy the localization of bromodomain inhibitors. These are cancer drugs that alter chromatin structure and gene

applied click chemistry methods toet al.localization within cells and across tissues. In a proof-of-concept study, Tyler Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug

Are better drugs just a click away?

ARTICLE TOOLS http://science.sciencemag.org/content/356/6345/1397

MATERIALSSUPPLEMENTARY http://science.sciencemag.org/content/suppl/2017/06/14/science.aal2066.DC1

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