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Condensin-driven remodelling of X chromosome topology during dosage compensation


The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure1,2. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half3,4,5,6,7. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes5,6. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (1 Mb) resembling mammalian topologically associating domains (TADs)8,9. TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.

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Figure 1: DCC modulates spatial organization of X chromosomes.
Figure 2: FISH shows DCC-dependent TAD boundaries at high-affinity rex sites.
Figure 3: Strong DCC-dependent interactions occur between high-affinity rex sites at TAD boundaries.
Figure 4: Quantitative FISH shows DCC-dependent association of rex sites in single cells.
Figure 5: DCC-dependent TADs influence global rather than local gene expression.

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Gene Expression Omnibus

Data deposits

Hi-C, ChIP-seq, and RNA-seq data are available at the NCBI Gene Expression Omnibus (GEO) repository, accession number GSE59716.


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We thank D. Mets for the computer script to analyse FISH data; A. Michel for the initial conformation experiments; D. Stalford for figures; Vincent J. Coates Genomics Sequencing Laboratory (NIH S10RR029668); and K. Brejc, T. Cline and A. Freund for manuscript comments. Research was supported in part by NIGMS grant R01 GM030702 to B.J.M. and NHGRI grant R01 HG003143 to J.D. B.J.M. is an investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations



E.C. conducted Hi-C, ChIP-seq and FISH experiments. Q.B. conducted FISH and rex-47 deletion experiments. R.P.M. conducted statistical and long-range interaction analyses. B.R.L. analysed Hi-C data and mapped TADs. B.S.W. conducted RNA-seq studies. E.J.R., S.U. and all authors analysed data and edited the manuscript, J.D. guided and performed Hi-C analysis and wrote manuscript sections. B.J.M. guided the study and wrote the manuscript.

Corresponding authors

Correspondence to Job Dekker or Barbara J. Meyer.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Genome-wide chromatin interaction maps for wild-type or DC mutant embryos and genome-wide difference chromatin interaction map.

a, b, Genome-wide chromatin interaction maps for wild-type embryos (a) and DC mutant embryos (b) from Hi-C data of two biological replicates pooled and binned at 50 kb and corrected with ICE. c, f, Scatter plots comparing normalized interactions between pairs of 50 kb bins in the two biological replicates from wild-type embryos (c) or DC mutant embryos (f) (both excluding x = y diagonal). A strong correlation between biological replicates is shown for wild-type embryos (Pearson’s correlation coefficient = 0.9854) and for DC mutant embryos (Pearson’s correlation coefficient = 0.9919). d, g, Overall interaction frequency decays with increasing genomic distance in wild-type embryos (d) and in DC mutant embryos (g). e, h, Cumulative reads versus linear genomic distance in wild-type embryos (e) and in DC mutant embryos (h). i, Genome-wide difference chromatin interaction map. Shown is the 50 kb binned heatmap depicting the Z-score difference between wild-type and DC mutant embryos (see Methods for Z-score difference calculation). The most apparent differences are on the X chromosome: blue signal within TADs (loss of intra-TAD interactions) and red signal between TADs (gain of inter-TAD interactions).

Extended Data Figure 2 Insulation profile calculation parameters and boundary calling.

a, Cartoon shows approach for calculating the insulation profile. A square is slid along each diagonal bin of the interaction matrix to aggregate the amount of interactions that occur across each bin (up to a specified distance upstream and downstream of the bin). Bins with a high insulation effect (for example, at a TAD boundary) have a low insulation score (as measured by the insulation square). Bins with low insulation or boundary activity (for example, in the middle of a TAD) have a high insulation score. Minima along the insulation profile are potential TAD boundaries. b, c, Heatmaps of chromosome X and chromosome I represent the insulation profiles calculated using insulation square sizes ranging from 10 kb to 1 Mb. At the 100 kb scale, weak boundaries are observed on the X chromosome and autosomes, but they are generally not changed in DC mutants. These boundaries cannot be detected at larger scales, meaning they do not insulate over distances beyond 100 kb (see e). These smaller scale structures may represent sub-TAD domains not correlated with dosage compensation. Boundaries called using a 500 kb insulation square represent TAD boundaries that define domains observed in chromosome-wide interaction maps of the X chromosome at 10 kb resolution. These boundaries are used in this paper (Fig. 1) and insulate over the larger distances defining the Mb-sized TADs. Boundaries on the X chromosome are the strongest and are DC dependent. df, Pile up plots depict aggregate (mean) Hi-C 10 kb Z-score data centred on specified ‘anchors’ (for example, rex sites, boundaries, changed boundaries). d, Pile up plots centred on all rex sites or top 25 rex sites in wild-type and DC mutant. e, Pile up plots centred on all boundaries called using insulation squares of 100 kb (left) or 500 kb (right) for chromosome X and chromosome I in wild-type and DC mutant. f, Pile up plots using boundaries called with a 500 kb insulation square, centred (left) on the single 10 kb bin at the midpoint of all 8 changed boundaries or (right) on all seven 10 kb bins within changed boundaries.

Extended Data Figure 3 TAD boundary analysis.

a, Insulation/delta plot of the 10 kb binned wild-type sample combined replicate chromosome X Hi-C data calculated using a 500-kb insulation square size. The insulation profile is depicted in black. In red, the ‘delta’ vector is depicted. It is derived from the insulation vector using a 200 kb delta window (see insulation methods). The ‘delta’ vector is used to facilitate the detection of the valleys/minima along the insulation profile. b, Cartoon example showing how the delta vector is calculated from the insulation data vector. For each bin (reference point) the average insulation differences are calculated between all points up to 100 kb left of the reference point relative to the reference point. The same is repeated for all points up to 100 kb right of the reference point. The delta value is then defined as the difference between the mean (left difference) and mean (right difference). c, Bar plot shows the distribution of distances between boundary calls obtained with biological replicate Hi-C data across all chromosomes. Dotted vertical line indicates that ±30 kb was chosen for boundary definition, as it was the window in which the majority of replicate boundary calls (>80%) overlap. d, Boxplots compare boundary strength (left) and spacing (right) in wild-type versus DC mutant embryos. Wild-type boundary strength on chromosome X (defined as the distance from the insulation minimum to the largest neighbouring maximum in the insulation profile) is higher than the DC mutant chromosome X boundary strength (P = 0.024) and higher than the boundary strength on wild-type autosomes (P = 0.03). TAD boundary strength on autosomes does not change in the DC mutant compared to the wild type (P = 0.979). Boundaries on chromosome X have less variance in spacing (interquartile range (IQR) = 253 kb) compared to the DC mutant (IQR = 525 kb) embryos. DC mutant X chromosome boundary spacing is more similar to the boundary spacing on the autosomes in wild-type embryos (IQR = 625 kb) and DC mutant embryos (IQR = 550 kb).

Extended Data Figure 4 Compartment and insulation analysis for chromosome I in wild-type embryos and DC mutant embryos.

a, ICE corrected chromatin interaction maps are shown for wild-type embryos and DC mutant embryos for both 10 kb binned and 50 kb binned data across replicate 1, replicate 2, and the combined replicates. b, Insulation profiles are shown for each biological replicate (replicate 1, orange line; replicate 2, blue line) for 50 kb and 10 kb binned data in wild-type embryos and DC mutant embryos. Insulation profiles are calculated using a 500 kb × 500 kb insulation square (10 bins × 10 bins for the 50 kb binned Hi-C data, and 50 bins × 50 bins for the 10 kb binned Hi-C data). The insulation profiles are consistent across replicates. Green tick marks, TAD boundaries identified using combined replicate data. c, Differential insulation plots derived from the insulation profiles calculated above (50 kb binned and 10 kb binned Hi-C data). d, 50 kb binned heatmap depicting the difference in chromatin interactions expressed as the difference in Z-scores between wild-type and DC mutant. e, Plot showing the compartment analysis calculated using the 50 kb binned wild-type Hi-C data. A/B compartment profile was determined by principle component analysis. First Eigen Vector value representing compartments (black) is plotted along the chromosome, revealing three zones for each autosome: two outer sections and the middle third of the chromosome. Positive Eigen1 signals represent the B (inactive compartment) and negative Eigen1 signals represent the A (active compartment). The compartments at chromosome ends display increased interactions with each other, both in cis and in trans (see Extended Data Fig. 1a). Also shown is the average binding of the lamin-associated protein LEM-2 along the chromosomes (grey). Overall compartmentalization correlates with LEM-2 binding, showing that compartments at both ends of chromosome I are located near the nuclear periphery.

Extended Data Figure 5 Compartment and insulation analysis for chromosome X in wild-type embryos and DC mutant embryos.

ae, See legend to Extended Data Fig. 4. In e, only two compartments are observed for chromosome X, compared to three for chromosome I. Overall compartmentalization correlates with LEM-2 binding, showing that the compartment at the left end of chromosome X is located near the nuclear periphery.

Extended Data Figure 6 Compartment and insulation analysis for chromosomes II, III, IV and V in wild-type embryos and DC mutant embryos.

ad, Chromosome II. eh, Chromosome III. il, Chromosome IV. mp, Chromosome V. a, e, i, m, Insulation profiles for each biological replicate (replicate 1, orange line; replicate 2, blue line) for 50 kb or 10 kb binned Hi-C data in wild-type embryos and DC mutant embryos. Green lines, TAD boundaries identified from combined replicate data. b, f, j, n, Differential insulation plots made from insulation profiles (50 kb binned or 10 kb binned Hi-C data). c, g, k, o, Plots show chromosome compartment analysis calculated with 50 kb binned data. Average binding of the lamin-associated protein LEM-2 is shown along the chromosomes (grey). Compartmentalization correlates with LEM-2 binding; compartments at both ends of autosomes are near the nuclear periphery. d, h, l, p, Heatmaps (50 kb bins) show differences in chromatin interactions as the differences in Z-scores (DC mutant minus wild-type embryos).

Extended Data Figure 7 rex sites are enriched at TAD boundaries and in top Hi-C interactions.

a, Tick plots rank the interaction Z-scores for the top 25 highest-affinity rex sites (black) among all other 10 kb bin Hi-C interactions on chromosome X (light blue). Bottom plot amplifies top 2,000 interactions. Density of black ticks (left) shows strong enrichment of rex–rex interactions among the most significant chromosome X interactions. b, Tick plots rank the Z-score differences (DC mutant minus wild-type embryos) for interactions between the top 25 rex sites among all other differences on chromosome X. Bottom plot amplifies top 2,000 changes. c, Quantification of Z-score differences for top 2,000 changes in (b). d, Bar graphs depict overlap between chromosome X TAD boundaries and rex sites. Three sets of TAD boundaries are shown: all 17 boundaries; 8 boundaries with an insulation change (DC mutant minus wild-type) >0.1; 5 boundaries present in wild-type embryos but absent in DC mutants. Overlap is calculated for the entire set of rex sites or just the top 25 rex sites. Percent of boundaries that overlap rex sites (left). Percent of rex sites that overlap each set of boundaries (right). Red bars, same sets of overlaps were calculated with 1,000 random sets of rex site positions along chromosome X. Average overlap and standard deviation are shown. No randomized set had as much overlap as the true rex set (P < 0.001). e, Cumulative comparison of Z-score differences for rex interactions and for 1,000 randomized sets of non-rex interactions (same number as in rex set). These rex or non-rex interactions had Z-scores >4 in wild-type embryos. rex interactions are reduced more in DC mutants than other similarly strong chromosome X interactions (P = 0.037; rex-interaction differences were significantly more reduced (KS test) than random interaction sets for 963 of 1,000 cases). f, 3D plots of Hi-C interaction profiles (normalized read counts) around top 25 rex sites for 2 Hi-C replicates of wild-type embryos or DC mutants. g, 3D plots of interactions between dox sites in wild-type embryos and DC mutants show no interaction peak. h, Cumulative plots show no difference in DC mutants for the distribution of autosomal Hi-C interaction Z-scores (10 kb bins) in TADs or at boundaries.

Extended Data Figure 8 Visualization and disruption of TAD boundaries.

ad, Visualization of DCC-dependent TAD boundaries in single cells confirms Hi-C analysis. a, Representative confocal images of embryonic nuclei of different genotypes stained with a DNA intercalating dye (blue) and FISH probes surrounding rex-32. Scale bar, 1 μm. b, Quantification of colocalization between FISH probes flanking rex-8 (see Fig. 2a) in XX and XO embryos confirms the DCC-dependent boundary identified by Hi-C. Because TADs on either side of rex-8 are small, we could only use one 500 kb FISH probe for each TAD. c, Quantification of colocalization between FISH probes for a TAD boundary on chromosome I (dashed line in d) in XX and XO embryos confirms the DCC-independent boundary identified by Hi-C. b, c, Box plots show the distribution of Pearson’s correlation coefficients between pairwise combinations of FISH probes. Boxes represent the middle 50% of coefficients, and the central bar within indicates the median coefficients (M). N, total number of nuclei. P values derived using the one-tailed Mann–Whitney U-test are shown below each graph. NS, not significant. d, Insulation difference plot of chromosome I for DC mutant insulation profile minus wild-type insulation profile. eg, Deletion of endogenous rex-47 by Cas9 disrupts DCC binding and TAD boundary formation. e, Schematic illustration of the sgRNA–Cas9 complex interacting with the rex-47 target sequence. f, Cas9-mediated deletion of rex-47. Top, diagram showing the location of DCC binding motifs within rex-47 (red bars) and Cas9-induced double strand break (arrow). Middle, diagram of the double-stranded repair template containing two 500 bp homology arms and an NcoI restriction site. Bottom, after precise homology-directed repair, a 419 bp region containing all DCC binding motifs was deleted and replaced with NcoI. g, Loss of DCC binding at endogenous locus carrying the rex-47 deletion. DCC binding at three 100 bp regions located upstream (a), within (b) or downstream (c) of the 419 bp deletion was examined using ChIP–qPCR. Histogram shows the ChIP–qPCR signal for DCC components DPY-27 or SDC-3 at target regions relative to the level at region b in wild-type embryos.

Extended Data Figure 9 Quantitative FISH shows that rex sites colocalize more frequently if the DCC is bound to chromosome X.

af, Data from histograms in Fig. 4b–g shown as cumulative plots. Number of nuclei and embryos (parentheses) assayed are shown (also for im). Distance between loci (red) and DCC dependence or independence of Hi-C interactions (black) are shown. P values (chi-squared test) compare values in the 0–300 nm bin to those in 301–2,700 nm bins. Same statistical analysis for (im). g, Correlation between DCC-dependent Hi-C interactions and DCC-dependent FISH colocalization. y axis, difference between wild-type and DC mutant Hi-C observed interaction frequency at 50 kb resolution. Higher number shows greater DCC-dependence. x axis shows two categories defined by FISH: sites with unchanged colocalization frequency in DC mutant (DCC-independent) (left); sites with less frequent colocalization in a DC mutant (DCC-dependent) (right). Red dotted line, cutoff for calling a Hi-C interaction ‘changed’ between the wild type and DC mutant. h, Scatter plot shows correlation between Hi-C and FISH data. y axis, Hi-C observed interaction frequency in 50 kb bins. x axis, percentage colocalization (that is, 300 nm bin) by FISH. R = 0.77 for all comparisons; R = 0.9 if the rex-47rex-8 interaction is omitted. im, Histograms show quantification of 3D distances between two FISH probes. i, j, Distant loci on chromosome X or chromosome I with weak Hi-C interactions. k, DCC-dependent interaction between X sites lacking DCC binding. lm, DCC-dependent interactions between distant rex sites.

Extended Data Figure 10 DCC-dependent TADs influence global rather than local gene expression.

Gene expression analysis was assayed using RNA-seq or GRO-seq, as indicated. a, b, Boxplots depict expression levels for wild-type or DC mutant embryos assayed by RNA-seq for chromosome X genes at changed TAD boundaries, unchanged TAD boundaries, all TAD boundaries or genes not at TAD boundaries. Expression levels are given as normalized read number per kilobase of gene length. c, Boxplots depict the fold change in expression assayed by RNA-seq between wild-type embryos and DC mutant embryos for genes at changed TAD boundaries, unchanged TAD boundaries, all TAD boundaries or genes not at boundaries. The lowest-expressing genes (bottom 10%) were removed from analysis. df, As in ac, but assayed by GRO-seq with gene expression levels given as fragments per kilobase of transcript per million mapped reads (FPKM). For af, P values were calculated using the Mann–Whitney U-test; significance did not withstand multiple testing correction. g, h, Boxplots depict the fold change in the gene expression between wild-type and DC mutant embryos based on RNA-seq or GRO-seq for chromsome X and chromosome I. Each box has genes from one TAD on chromosome X (left) or chromosome I (right). Lowest-expressing genes (bottom 10%) were removed from analysis. No discernible pattern was evident for expression changes versus gene location. i, Boxplots depict the fold change in chromosome X gene expression between wild-type embryos and DC mutant embryos relative to the distance from the TAD boundary. Each box contains genes in 10 kb bins radiating out from the centre of each TAD boundary. The lowest-expressing genes (bottom 10%) were removed from analysis. No discernible pattern to the gene expression changes exists, as assayed by RNA-seq (left) or GRO-seq (right). Weak significance and lack of concordance between RNA-seq and GRO-seq data suggest no biologically relevant correlation between TAD boundaries and local regulation of gene expression.

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Crane, E., Bian, Q., McCord, R. et al. Condensin-driven remodelling of X chromosome topology during dosage compensation. Nature 523, 240–244 (2015).

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