NEUROBIOLOGY

Chromatin remodelinginactivates activity genesand regulates neural codingYue Yang,1* Tomoko Yamada,1*† Kelly K. Hill,1,2 Martin Hemberg,3 Naveen C. Reddy,1

Ha Y. Cho,1 Arden N. Guthrie,1 Anna Oldenborg,1 Shane A. Heiney,4 Shogo Ohmae,4

Javier F. Medina,4 Timothy E. Holy,1 Azad Bonni1‡

Activity-dependent transcription influences neuronal connectivity, but the roles andmechanisms of inactivation of activity-dependent genes have remained poorly understood.Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling anddeacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation. Purification of translating messengerRNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditionalknockout of the coreNuRD subunit Chd4 impairs inactivation of activity-dependent geneswhenneurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activitygenes impairs dendrite pruning. Imagingof behavingmice revealedhyperresponsivityof granuleneurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigeneticmechanism that inactivates activity-dependent transcription and regulates dendrite patterningand sensorimotor encoding in the brain.

Neuronal activity influences transcriptionin neurons, and hence regulates neuralcircuits (1, 2). Activity-dependent genesare often rapidly transcribed and thenrapidly inactivated (3, 4). However, atten-

tion has focused on the induction of transcrip-tion (1, 5–7) rather than the biological roles andmechanisms of inactivation of activity-dependenttranscription.Epigenetic regulators, including adenosine

5′-triphosphate (ATP)–dependent chromatin-remodeling enzymes (8, 9), are ideally suitedto orchestrate the effects of neuronal activity ontranscription globally. The ATP-dependent nucleo-some remodeling and deacetylase (NuRD) com-plex triggers alterations of histone modifications,resulting in promoter or enhancer decommission-ing and prolonged silencing of transcription (10–15).To probe the role of the NuRD complex in

dynamic regulation of transcription in the brain,we characterized the genome-wide occupancy ofthe core NuRD ATPase-encoding subunit, Chd4,in the mouse cerebellum. A substantial number ofregions (9842) occupied by Chd4 in the cerebellumoverlapped with transcription start sites (TSSs)(fig. S1A). Nearly all Chd4-bound TSSs (96%)harbored the histone modification H3K4 (histoneH3 lysine 4) trimethylation (H3K4me3), whichmarks active and poised promoters (16, 17), butnot H3K27 trimethylation (H3K27me3), which

marks inactive promoters (18) (Fig. 1A and fig.S1, B and C). Chd4 binding at H3K4me3-enrichedTSSs was diminished in the cerebellum in micein which Chd4 was conditionally deleted ingranule neurons (Fig. 1, A and B, and fig. S1, Dto H). Chd4 binding at H3K4me3-enriched TSSsin the cerebellum correlated tightly with acetyla-tion of H3K9 and H3K14 (H3K9/14ac), whichmarks actively transcribed loci (19), and with geneexpression (Fig. 1C and fig. S1I). Thus, Chd4 oc-cupies the promoters of most actively transcribedgenes in the mouse brain.The NuRD complex triggers the sustained re-

pression of only a small set of <200 genes in thecerebellum through diminution of H3K9/14acand H3K4me3 at these promoters (13). We, there-fore, reasoned that the NuRD complex might op-erate through another epigenetic mechanism toregulate the much larger set of Chd4-bound activegenes. Exchange of the histone variant H2A.z isassociated with regulation of transcription (20–23).H2A.z was enriched at 97% of Chd4-bound pro-moters in the mouse cerebellum (fig. S1J). Chd4knockout decreased H2A.z and acetylated H2A.zenrichment at promoters with high Chd4 occu-pancy (Fig. 1, D and E), but not at most en-hancers in the cerebellum (fig. S2).We next intersected RNA sequencing (RNA-Seq)

(13) and H2A.z chromatin immunoprecipita-tion (ChIP)–Seq analyses in the mouse cerebel-lum of conditional Chd4 knockout and controllittermate mice. Although a small group of 121up-regulated genes in conditional Chd4 knockoutmice harbored increased H2A.z enrichment attheir promoters, a much larger group of 1233 up-regulated genes displayed reduced H2A.z enrich-ment at TSSs (Fig. 1F and fig. S3, A and B). Geneontology analyses revealed that genes with re-duced H2A.z enrichment encoded proteins that

function in intracellular signaling cascades, cellcycle control, and phosphorylation (fig. S3C). No-tably, there was little or no change in H3K9/14ac,H3K4me3, and H3K27me3 or in the density ofhistone H3 at the promoters of these genes uponChd4 knockout (Fig. 1G and fig. S3, D to G). To-gether, these data indicate that the NuRD complextriggers the deposition of H2A.z at the promotersof a large group of actively transcribed signalinggenes and inactivates their expression in the brainin vivo.The identification of an epigenetic link from

the NuRD complex to H2A.z at the promoters ofsignaling genes led us to investigate whether theNuRD complex regulates transcription dynam-ically in response to neuronal activity. Expressionof the activity-dependent genes c-fos, nr4a1, dusp1,and nfil3 was increased in granule neurons of therodent cerebellum upon membrane depolarizationand rapidly inactivated 1 hour after cessation ofmembrane depolarization (Fig. 2A). Depletionof Chd4 or Mbd3, another subunit of the NuRDcomplex (24), impaired inactivation, but not re-activation, of activity genes in neurons aftermembrane depolarization (Fig. 2A and figs. S4and S5, A and B). Thus, the NuRD complex ap-pears to be required for inactivation of activity-dependent genes in neurons.In chromatin immunoprecipitation followed

by quantitative polymerase chain reaction (ChIP-qPCR) analyses, H2A.z increased at the promotersof the c-fos, nr4a1, and dusp1 genes in granuleneurons during the inactivation phase after mem-brane depolarization (fig. S5C). Depletion of Chd4reduced H2A.z enrichment, but not histone H3,at the promoters of the c-fos, nr4a1, and dusp1genes in neurons during the inactivation phase(Fig. 2B) but not the activation phase (fig. S5D).Thus, the NuRD complex appears to specificallystimulate the loading of H2A.z at the promotersof activity-dependent genes during the inactiva-tion phase of transcription.Depletion of H2A.z by RNA interference (RNAi)

in neurons increased expression of the c-fos, nr4a1,dusp1, and nfil3 genes during the inactivationphase of activity-dependent transcription, withlittle or no effect during activation or reactivation(Fig. 2C and fig. S6). Thus, the NuRD complex andH2A.z are required for inactivation of activity-dependent gene expression in neurons.We next used a rotarod procedure to induce

neuronal activity in the mouse cerebellum (Fig. 2D).RNA-Seq analyses from the cerebellum of micerunning on a rotarod for 1 hour compared to micehoused in a cage revealed increased transcriptionof activity genes (Fig. 2E), and these genes wereinactivated within 1 hour after rotarod activitystopped. Chd4 knockout increased the expressionof c-fos, fosl2, and dusp1 in the cerebellum aftercessation of rotarod activity but not during theactivation phase of rotarod-induced transcrip-tion (Fig. 2F). Thus, the NuRD complex affectsspecifically the inactivation of activity genes inthe brain.We next tested whether NuRD-dependent in-

activation of activity genes might regulate granuleneuron connectivity in the cerebellum. We

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1Department of Neuroscience, Washington University Schoolof Medicine, St. Louis, MO 63110, USA. 2MD-PhD Program,Washington University School of Medicine, St. Louis, MO63110, USA. 3Wellcome Trust Sanger Institute, Hinxton CB101SA, UK. 4Department of Neuroscience, Baylor College ofMedicine, Houston, TX 77030, USA.*These authors contributed equally to this work. †Present address:Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan. ‡Corresponding author. Email: bonni@wustl.edu

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determined the stage of granule neuron matu-ration in vivo during which the NuRD complexregulates activity-dependent transcription. Weused in vivo electroporation and translating ribo-somal affinity purification (25) to characterizegene expression in developmentally synchronizedgranule neurons in vivo (Sync-TRAP) (Fig. 3A andfig. S7, A and B). Sync-TRAP followed by qPCRor by RNA-Seq analyses of the cerebellum inmice 6 days after electroporation revealed thatexpression of granule neuron–specific genes wasenriched (fig. S7C), and led to the identificationof chromatin regulators and ubiquitin ligasesenriched in developing granule neurons (Fig.3B and fig. S7D). Sync-TRAP-Seq analyses inChd4loxP/loxP mice electroporated with the re-combinase Cre revealed that 86% of significantly

differentially expressed genes were up-regulatedupon conditional Chd4 knockout (Fig. 3C andfig. S7E). Sync-TRAP-Seq and Sync-TRAP-qPCRanalyses revealed that transcription of the activity-dependent npas4, nfil3, c-fos, and nr4a1 genes,but not of granule neuron–specific genes, wasincreased in granule neurons depleted of Chd4in vivo (Fig. 3, D and E). Immunohistochemicalanalyses confirmed that c-Fos protein was up-regulated in Chd4-depleted granule neurons invivo (fig. S8, A and B). Sync-TRAP-qPCR analysesalso revealed that depletion of H2A.z increasedc-fos gene expression in granule neurons in vivo(fig. S8C). The NuRD complex and H2A.z thusappear to trigger the inactivation of activity-dependent genes in synchronously developing gran-ule neurons in the mouse cerebellum.

Because the NuRD/H2A.z epigenetic link reg-ulates activity-dependent transcription in a tem-poral window of dendrite morphogenesis in thecerebellum, we asked whether NuRD-dependentinactivation of genes might influence dendritepatterning and connectivity. Granule neuronslabeled by in vivo electroporation undergo dis-tinct stages of dendrite morphogenesis in a syn-chronized manner in vivo (Fig. 4A and fig. S9, Ato C). Depletion of Chd4 increased the totallength of granule neuron dendrites and thenumber of primary dendrites during the periodof pruning, with little or no effect on the de-velopment of granule neuron dendrites duringearlier stages (Fig. 4B and fig. S9, A to C). Ex-pression of NuRD-regulated activity genes alsoimpaired dendrite pruning in vivo (Fig. 4, C

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Fig. 1. The core NuRD subunit Chd4 occupies promoters of activelytranscribed genes in the cerebellum in vivo. (A) University of California,Santa Cruz (UCSC) genome browser tracks at the bdnf locus in the cerebellumof conditional Chd4 knockout and control mice. (B) Location of Chd4 bindingnear the TSSs of H3K4me3-enriched genes in the cerebellum. In all ChIP-Seqanalyses, shading denotes SE. (C) Comparison of Chd4 and H3K9/14ac readdensities at H3K4me3-enriched genes. (D and E) Comparison of Chd4 andH2A.z [(D), P < 0.01, Hotelling T2 test for small sample size] or acetylated H2A.z

(E) read density at H3K4me3-enriched TSSs in conditional Chd4 knockout andcontrol mice. (F) Comparison of the fold change in H2A.z read density and foldchange in gene expression atH3K4me3-enriched TSSs in postnatal day 22 (P22)conditional Chd4 knockout and control mice. Genes with reduced H2A.z [foldchange (log2) < –0.585] upon conditional Chd4 knockout are highlighted in blue,and genes with increased H2A.z (fold change (log2) > 0.585) are highlighted ingreen. (G) The profile of H2A.z, H3K9/14ac, H3K4me3, and H3K27me3 sur-rounding the TSSs of the group of genes indicated in (F) highlighted in blue.

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and D). In contrast, upon expression of NuRD-repressed target genes not known to be regulatedby activity or other cerebellum-enriched tran-scriptional regulators, only one increased den-drite length but not dendrite number (Fig. 4, Cand D, and fig. S9D). These results indicate thatNuRD-dependent inactivation of activity genesmay drive granule neuron dendrite pruning inthe cerebellum.

We next characterized the consequences ofNuRD actions on responses of granule neuronsin behaving mice. Mature granule neurons receiveon average four mossy fiber inputs, which is op-timal for sparse, lossless encoding of sensori-motor information (26). We electroporated mousepups with a plasmid encoding the calcium in-dicator GCaMP6s together with an mCherryexpression plasmid, and subjected mice to a

motorized treadmill task (Fig. 5A and movie S1).After habituation, two-photon imaging of lobuleVI in the mouse cerebellum revealed that a setof GCaMP6s-labeled granule neurons was activeduring locomotion (Fig. 5, B and C). ConditionalChd4 knockout triggered a robust increase inthe fraction of high-fidelity treadmill-responsivegranule neurons and concomitantly reducedthe fraction of unresponsive granule neurons

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Fig. 2. The NuRD/H2A.z chromatin-remodeling pathway inactivatesactivity-dependent genes in neurons. (A) Granule neurons from P5 rat pupstransfected with the U6/chd4, U6/mbd3, or the control U6 RNAi plasmid weredepolarized (dep on) with 50 mM KCl for 1 hour and then switched back tohyperpolarizing media (dep off) for 1 hour and subjected to quantitativereverse transcription (qRT)–PCR analyses. Expression of c-fos, nr4a1, dusp1,and nfil3 genes upon cessation ofmembrane depolarization in neurons afterknockdown of the NuRD subunits Chd4 and Mbd3 (*P < 0.05, analysis ofvariance (ANOVA) followed by Fisher’s protected least significant difference(PLSD) post hoc test, n = 3 independent experiments). (B) Lysates of granuleneurons transfected with the U6/chd4 or control U6 RNAi plasmid and treatedas in (A) were subjected to ChIP-qPCR analyses with antibody to H2A.z

(top) or to histone H3 (bottom) and primers specific to the c-fos, nr4a1, anddusp1 gene promoters or a c-fos control region (*P < 0.05, t test, n = 3independent experiments). (C) Expression of c-fos, nr4a1, fosl2, dusp1, andnfil3 genes upon cessation of membrane depolarization in granule neuronsafter knockdown of H2A.z (*P < 0.05, t test, n = 3 independent experi-ments). (D and E) The cerebellum of P27-P28 mice trained on the rotarodtask (D) was subjected to RNA-Seq analyses. A heatmap of the expressionlevels of significantly differentially expressed genes (E) [false discovery rate(FDR) < 0.05, fold change > 2 for rotarod compared to control homecage, n =4 mice, base 2 log-transformed mean centered]. (F) The cerebella of con-ditional Chd4 knockout or control mice trained on the rotarod task weresubjected to qRT-PCR analyses (*P < 0.05, t test, n = 6 to 8 mice).

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(Fig. 5, C and D). Thus, inhibition of the NuRDcomplex leads to hyperresponsivity of granuleneurons to sensorimotor stimuli.In behavior analyses, depletion of Chd4 in

granule neurons impaired procedural learning, in-cluding in the accelerating rotarod and delay eye-

blink conditioning assays, but had little or no effecton motor coordination as assessed in the DigiGaitand open field assays (fig. S10).Our study defines chromatin-remodeling events

that inactivate activity-dependent transcriptionand control dendrite architecture and sensori-

motor encoding in the brain (see model in Fig.5E). Our findings suggest that inactivation ofactivity genes is essential for the maturation ofgranule neuron dendrite arbors and in the con-trol of neural circuit activity in response to sen-sorimotor signals. We have uncovered the NuRD

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Fig. 3. In vivo Sync-TRAP analyses reveal that the NuRD complex inacti-vates activity-dependent genes in synchronously developing granuleneurons in the cerebellum. (A) A schematic depicting the Sync-TRAP pro-tocol. In vivo electroporation of mouse pups with the green fluorescent protein(GFP)–Rpl10a expression vector labels granule neuron precursors localized inthe external granule layer (EGL). Labeled granule neurons migrate to theinternal granule layer (IGL) and undergo differentiation in a synchronizedman-ner (see fig. S9A). mRNAs bound to GFP-labeled ribosomes were profiled tocharacterize the in vivo gene expression program in synchronously developinggranule neurons. (B to E) Sync-TRAP followed by RNA-Seq or qPCR analyseswith Chd4loxP/loxP mice electroporated with the pCAG-Cre or control vector.

Scatterplot of input RNA reads per kilobase of transcript per million mappedreads (RPKM) and immunoprecipitated mRNA RPKM subjected to RNA-Seqanalyses (B). Scatterplot of immunoprecipitated mRNA RPKM from Cre-expressing orcontrol granule neurons subjected toRNA-Seqanalyses (C).Genesthat are less abundant in control electroporated granule neurons compared toinput (B) and increased upon knockout of Chd4 compared to control (C) aredenoted in light blue. Diagonal lines represent 0.5-, 1-, and 2-fold changes in thegeometric mean of gene expression between conditions [(B) and (C), red circlesdenote FDR < 0.05]. Fold changes in gene expression of NuRD targets identifiedby Sync-TRAP followed by RNA-Seq (D). Validation of NuRD-regulated activity-dependent genes with Sync-TRAP followed by qPCR analyses (E).

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Fig. 5. The NuRD com-plex promotes sparsesensorimotor encodingin behaving mice.(A) Schematic of theparadigm for in vivo two-photon calcium imagingduring treadmill walking.Granule neurons of lobuleVI of the cerebellum elec-troporated with theGCaMP6s and mCherryexpression plasmids(inset). Scale bar: 50 mm.(B) Ca2+ transients ofthree representative cellsin response to 10-streadmill-on stimulus(gray: individual trials;black: trial mean; greenpanel: treadmill-onperiod). (C and D)P10–P11 Chd4loxP/loxP

mice were electroporatedwith the Cre expressionplasmid or control vectortogether with theGCaMP6s and mCherryexpression plasmids. Heatmap of maximum change in fluorescence DF/F (C) during treadmill-on stimulus compared to preceding treadmill-off period for five trialsper neuron in conditional Chd4 knockout and control mice and corresponding neuronal responsivity distributions (D) (Chi-Square test of independence P <0.00001, n = 5 mice, 199 to 520 somas). Error bars represent SE from bootstrap test. (E) Model of the NuRD complex and H2A.z chromatin-remodeling link in theregulation of activity-dependent transcription and neural circuit assembly and function.

Fig. 4. NuRD-dependent inactivation of activity genesdrives granule neuron dendrite pruning in the cere-bellum in vivo. (A) Granule neuron precursors weretransfected by in vivo electroporation (left), and post-mitotic granule neuronmorphologywasvisualized (cameralucida drawings on right).The migration (stage 1), dendritegrowth (stage 2), and dendrite pruning (stage 3) of granuleneurons are depicted. (B) P6 Chd4loxP/loxP mice wereelectroporatedwith theCre expression plasmid orcontrol

vector together with the GFP expression plasmid and subjected to immunohistochemistry with antibody to GFP. Representative images (left) and quantification(right, *P < 0.01, t test, n = 3 mice). (C andD) P7 rat pups were electroporated with a panel of six activity-dependent genes or 12 other NuRD targets and analyzedas in (B). Representative images (C) and quantification [(D), *P < 0.05, ANOVA followed by Fisher’s PLSD post hoc test, n = 3 to 4 rats). Scale bars: 10 mm.

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complex and H2A.z as epigenetic regulators thatmediate the inactivation of activity genes in thebrain. Thus, epigenetic mechanisms may have anactive role in the inactivation of gene expressionin the brain following neuronal activity.

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ACKNOWLEDGMENTS

We thank members of the Bonni laboratory for helpfuldiscussions and critical reading of the manuscript and E. Han for

advice in imaging analyses. Supported by NIH grant NS041021(A.B.), the Mathers Foundation (A.B.), NIH grant MH093727(J.F.M.), and NIH Medical Scientist Training Program grant T32GM07200 (K.K.H.). We thank the Genome Technology AccessCenter at Washington University, which is supported by NationalCancer Institute grant P30 CA91842 to the Siteman Cancer Centerand by Institute of Clinical and Translational Sciences–Clinicaland Translational Science Awards UL1TR000448. The authorsdeclare no conflicts of interest. Raw sequencing data related tothis study have been archived in the Gene Expression Omnibus(GEO) database under accession number GSE83253 (available atwww.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE83253).

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/353/6296/300/suppl/DC1Materials and MethodsFigs. S1 to S10Tables S1 and S2References (27–43)Movie S1

11 September 2015; accepted 12 May 201610.1126/science.aad4225

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Chromatin remodeling inactivates activity genes and regulates neural coding

Shane A. Heiney, Shogo Ohmae, Javier F. Medina, Timothy E. Holy and Azad BonniYue Yang, Tomoko Yamada, Kelly K. Hill, Martin Hemberg, Naveen C. Reddy, Ha Y. Cho, Arden N. Guthrie, Anna Oldenborg,

DOI: 10.1126/science.aad4225 (6296), 300-305.353Science 

, this issue p. 300; see also p. 218Sciencea treadmill.resulted in hypersensitivity of mice to sensory stimuli and excessive neuronal connectivity in animals performing a task onvariant H2A.z at promoters of activity-dependent genes required the NuRD complex. Loss of the NuRD complex function activity-dependent transcription in the mouse cerebellum (see the Perspective by Sweatt). Deposition of the histonechromatin remodeling by the nucleosome remodeling and deacetylase complex (NuRD) in the inactivation of such

propose a role foret al.connections between neurons, and such modifications can influence animal behavior. Yang The activity of neurons in the brain controls the transcription of genes that influence the pruning of dendritic

Epigenetic regulation in the brain

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