Nuclear compartmentalization of active and inactive chromatin is thought to occur through microphase separation mediated by interactions between loci of similar type. The nature and dynamics of these interactions are not known. We developed liquid chromatin Hi-C to map the stability of associations between loci. Before fixation and Hi-C, chromosomes are fragmented, which removes strong polymeric constraint, enabling detection of intrinsic locus–locus interaction stabilities. Compartmentalization is stable when fragments are larger than 10–25 kb. Fragmentation of chromatin into pieces smaller than 6 kb leads to gradual loss of genome organization. Lamin-associated domains are most stable, whereas interactions for speckle- and polycomb-associated loci are more dynamic. Cohesin-mediated loops dissolve after fragmentation. Liquid chromatin Hi-C provides a genome-wide view of chromosome interaction dynamics.
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All code for data processing and analysis, described in detail in the Methods, is available through the following GitHub accounts:
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J.D. and J.F.M. acknowledge support from the National Institutes of Health Common Fund 4D Nucleome Program (U54-DK107980). This work was also supported by a grant from the National Human Genome Research Institute (NHGRI) to J.D. (HG003143) and to Z.W. (HG009446), and by grants from the National Cancer Institute (U54-CA193419) and from the National Institutes of Health (R01-GM105847 to J.F.M. and K99-GM123195 to A.D.S.). J.D. is an investigator of the Howard Hughes Medical Institute. We thank L. A. Mirny and E. J. Banigan for discussions, and J. Ma for sharing K562 sub-compartment assignments.
The authors declare no competing interests.
Peer review information Nature Genetics thanks Bing Ren and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a, Hi-C 2.0 intra-chromosomal interaction maps for K562 cells (top) and purified nuclei (bottom). b, 5 C interaction map of 1 Mb region surrounding the beta-globin locus in K562 cells. Top: cells. Bottom: purified nuclei. CTCF-mediated interactions are preserved in purified nuclei. Red circles: positions of CTCF sites, purple square Beta-globin locus control region (LCR). c, Representative 3C-PCR (out of two experiments) for a 44,120 kb region surrounding the beta-globin LCR on chromosome 11, detects at high resolution the known looping interactions between the LCR and the expressed gamma-globin genes (HBE1, HBG2) in K562 cells. Looping interactions are not detected in GM12878 cells that do not express these genes. Top: cells. Bottom: purified nuclei. Each data point is the average of 3 PCR reactions; error bars indicate standard error of the mean. d, Compartmentalization saddle plots: average intra-chromosomal interaction frequencies between 100 kb bins, normalized by genomic distance. Bins are sorted by their PC1 value derived from Hi-C data obtained with K562 cells. In these plots preferential B-B interactions are in the upper left corner, and preferential A-A interactions are in the lower right corner. Numbers in the corners represent the strength of AA interactions as compared to AB interactions and BB interactions over BA interactions. Left: cells. Right: purified nuclei. e, Spearman correlation of PC1 in cells vs PC1 in nuclei for chromosome 2 at 100 kb resolution (ρ = 0.99).
a, Workflow for Liquid chromatin Hi-C. b, Illustration of loss of structure metric using a pre-digested sample and a control. c, Hi-C interaction maps and compartmentalization saddle plots for a second replicate of control nuclei (incubated for 4 hours in restriction buffer) and nuclei pre-digested with HindIII for 4 hours. d, Left: Spearman correlation of DpnII restriction digestion efficiency (DpnII-seq) and PC1 for chromosome 2 at 40 kb resolution. Right: Partial correlation of LOS (LOS residuals) with PC1 after controlling for restriction efficiency (DpnII-seq), for chromosome 2 at 40 kb resolution. Spearman correlation is indicated. e, compartmentalization saddle plots for the corresponding conditions. Numbers indicate strength of A-A and B-B interactions for inter-chromosomal interactions.
a, Schematic of DpnII-seq experimental protocol for recovering DNA fragments digested by the restriction enzyme DpnII. b, Directed graph of DpnII-seq computational pipeline. c, Histogram of distance to nearest DpnII recognition site for each recovered DpnII digested fragment. d, Raw DpnII-seq signal displaying multiple copy number states (2 N, 3 N, 4 N) within chromosome 3 (data binned at 40 kb). e, Copy number corrected DpnII-seq signal displaying single copy number state (2 N) across chromosome 3.
a, DNA purified from nuclei pre-digested with DpnII for 4 hours were separated into slices of three sizes and run on a Fragment Analyzer. One experiment was performed. b, Fragment Analyzer distributions of DNA fragment sizes for the three separated slices (RFU: relative fluorescence unit, LM: lower marker, fragment sizes at distribution peaks are given in blue). c, Top plot: Eigenvector 1 values (PC1, 40 kb resolution) across a section of chromosome 2, representing A (red) and B (blue) compartments. Bottom three plots: Normalized coverage of fragments from given slice size across a section of chromosome 2. d, Percentages of fragments mapped to each subcompartment for given slice size. e, Top plot: LOS along chromosome 2 at 40 kb resolution for nuclei pre-digested with DpnII. Middle plot: Average fragment size estimated for every 40 kb bin after pre-digestion with DpnII (Methods). Bottom plot: LOS-residuals for nuclei pre-digested with DpnII after correction for average fragment size. f, Boxplot of average fragment size for A compartment bins (n = 35836) and B compartment bins (n = 33252). Significance determined by two-sample two tailed t-test (p < 2.2e-16, t = -80.535, d.f. = 67270, 95% CI = -0.1228385,-0.1170014). Boxplot middle line is the median, the lower and upper edges of the box are the first and third quartiles, the whiskers extend to interquartile range (IQR) × 1.5 from the box. Outliers are represented as points. g, Left plot: correlation between LOS for nuclei pre-digested with DpnII and average fragment size. Grey line indicates moving average used for residual calculation. Right plot: partial correlation between residuals of LOS for nuclei pre-digested with DpnII and residuals of PC1 after correcting for correlations between LOS and average fragment size and PC1 and average fragment size (for chromosome 2, Spearman correlation values are indicated). h, Left plot: Correlation between DpnII-seq signal and average fragment size. Right plot: correlation between residuals of LOS after correcting for average fragment size and residuals of LOS after correcting for DpnII-seq signal (for chromosome 2, Spearman correlation values are indicated). i, Partial correlation between residuals of t1/2 and residuals of PC1 after correcting for correlations between t1/2 and average fragment size and PC1 and average fragment size.
Extended Data Fig. 5 Liquid chromatin Hi-C results are reproducible using the restriction enzyme FatI.
a, Restriction sites for the selected restriction enzymes. Black triangles denote cut sites. b, Top plot: Eigenvector 1 values (PC1, 40 kb resolution) across a section of chromosome 2, representing A (red) and B (blue) compartments. Bottom three plots: Coverage of restriction sites (40 kb resolution). Spearman correlation between restriction site coverage and PC1 is given for each restriction site track. c, Third replicate of DpnII predigest liquid chromatin Hi-C. Hi-C interaction maps of chromosome 2 binned at 500 kb. Bottom left: control nuclei in restriction buffer for 4 hours. Top right: nuclei digested for 4 hours with DpnII prior to Hi-C. Left track: Eigenvector 1 values (PC1, 40 kb resolution) across a section of chromosome 2, representing A (red) and B (blue) compartments. d, Top plot: LOS along chromosome 2 at 40 kb resolution for nuclei pre-digested with DpnII. Middle plot: DpnII-seq signal. Bottom plot: LOS-residuals for nuclei pre-digested with DpnII after correction for DpnII-seq signal. e, FatI predigest liquid chromatin Hi-C. Hi-C interaction maps of chromosome 2 binned at 500 kb. Bottom left: control nuclei in restriction buffer for 4 hours. Top right: nuclei digested for 4 hours with FatI prior to Hi-C. Left track: Eigenvector 1 values (PC1, 40 kb resolution) across a section of chromosome 2, representing A (red) and B (blue) compartments. f, Top plot: LOS along chromosome 2 at 40 kb resolution for nuclei pre-digested with FatI. Middle plot: FatI-seq signal. Bottom plot: LOS-residuals for nuclei pre-digested with FatI after correction for FatI-seq signal. g, Left plot: Correlation between LOS for nuclei pre-digested with DpnII and PC1. Right plot: partial correlation between residuals of LOS for nuclei pre-digested with DpnII and residuals of PC1 after correcting for correlations between LOS and DpnII-seq and PC1 and DpnII-seq signal (for chromosome 2, Spearman correlation values are indicated). h, Left plot: Correlation between LOS for nuclei pre-digested with FatI and PC1. Right plot: partial correlation between residuals of LOS for nuclei pre-digested with FatI and residuals of PC1 after correcting for correlations between LOS and FatI-seq and PC1 and FatI-seq signal (for chromosome 2, Spearman correlation values are indicated). i, Correlation between LOS for nuclei pre-digested with FatI and LOS for nuclei pre-digested with DpnII (genome wide, Spearman correlation values are indicated). j, Correlation between residuals of LOS for nuclei pre-digested with FatI and residuals of LOS for nuclei pre-digested with DpnII after correcting for correlations between FatI LOS and FatI-seq and DpnII LOS and DpnII-seq (genome wide, Spearman correlation values are indicated).
a, DpnII-seq signals along chromosome 2 after indicated times of digestion. Spearman correlations between DpnII-seq and t1/2 at each timepoint is indicated. b, t1/2 residuals along chromosome 2 after correcting t1/2 values by the correlation between t1/2 and DpnII-seq signals shown on the left obtained after the indicated times of digestion. Spearman correlation between t1/2 residuals and PC1 residuals are indicated. c, Top: Genome wide scatterplot of t1/2 versus 1 hour DpnII-seq signal. Gray line: moving average. Bar plot above shows the number of loci displaying various levels of DpnII-mediated cuts. Bottom: residuals of t1/2 calculated by subtracting t1/2 from the corresponding average t1/2 (gray line in top plot) plotted vs. number of DpnII cuts. Red dots: loci in the A compartment; Blue dots: loci in the B compartment. The majority of loci have 500-1100 cuts. When comparing loci with similar number of DpnII cut we observe that loci in the A compartment have shorter t1/2 values as compared to loci in the B compartment. d, Top: LOS along chromosome 2 at the indicated timepoints of digestion and calculated by comparison to Hi-C data obtained after 1 hour of digestion. Middle: calculation of t1/2 from LOS at different timepoints. Bottom: t1/2 along chromosome 2. This t1/2 is calculated using the Hi-C data obtained after 1 hour of pre-digestion as starting point. e, Partial correlation between LOS and PC1 after correcting for their correlations with DpnII-seq. LOS (at 2 hours) is calculated as in panel C using the Hi-C data obtained after 1 hour of pre-digestion as starting point. f, Partial correlation between t1/2 and PC1 after correcting for their correlations with DpnII seq. t1/2 is calculated as in panel D using the Hi-C data obtained after 1 hour of pre-digestion as starting point. Spearman correlations are indicated.
Extended Data Fig. 7 Liquid chromatin-Hi-C protocol and quantification of loss of structure after chromatin pre-digestion.
a, Workflow for Liquid chromatin Hi-C timecourse. CL = cross-linking step. b, Compartment strength derived from compartment saddle plots (See Methods). Left: Diagram depicting compartment strength calculation for B-B interactions. Plot to the right of diagram: B-B interaction strength as a function of bin number for all timepoints of the time course. Right: Diagram depicting compartment strength calculation for A-A interactions. Plot to the right of diagram: A-A interaction strength as a function of bin number for all time points of the time course. c, Top: LOS signal across a 40 Mb region on chromosome 2 calculated for indicated timepoints in the digestion timecourse. Line colors as in Fig. 4e. Bottom: Exponential curve fit to LOS timepoints for a single 40 kb bin. t1/2 (dashed vertical blue line) representing time elapsed to reach half saturation of LOS signal. d, Left: Density distributions of t1/2 for A and B compartments. Right: t1/2 saddle plots: average intra-chromosomal interaction frequencies between 40 kb bins, normalized by genomic distance. Bins are sorted by their t1/2 value derived from digestion timecourse. Bins with high t1/2 preferentially interact (bottom right of heatmap) and bins with low t1/2 preferentially interact (top left of heatmap). e, Scatterplot of t1/2 vs t1/2 for two timecourse replicates (R1 and R2) on chromosome 2. Regression line (red). Spearman correlation is indicated. f, Scatterplot of PC1 vs t1/2 for chromosome 2. A compartment (red); B compartment (blue). g, Left: Scatterplot of percent interactions occurring in cis within a 6 Mb distance out of total genome wide interactions for each 40 kb bin in control Hi-C map (Cis %) vs PC1. Middle: Cis% vs t1/2. Right: Scatterplot of partial correlation between PC1 and t1/2 controlled by Cis %. A compartment (red); B compartment (blue). Solid red lines are regression lines. Spearman correlations are indicated.
Extended Data Fig. 8 Associations between sub-nuclear structures and chromatin interaction stability.
a, Spearman correlation matrix between signals for various chromatin state markers of various sub-nuclear structures, chromatin remodellers and histone modifications with row order determined by hierarchical clustering. b, The genome was split into 16 bins, where each bin corresponds to sets of loci that share the same t1/2 interval. For each t1/2 interval the mean z-score signal enrichment for various markers of sub-nuclear structures, chromatin remodellers and histone modifications was calculated and shown as a heatmap. Row order determined by hierarchical clustering. c, 3 Mb region surrounding HoxD locus. Top: Hi-C contact map for K562 control nuclei showing the position of the HoxD locus. Tracks: ChIP-seq tracks for polycomb subunits (cyan) and the polycomb associated histone modification H3K27me3 (green). t1/2 (blue). Minus strand and plus-strand signal of total RNA-seq (red). Refseq Genes (blue/black). The polycomb-bound domain displays shorter half-life compared to expressed genes in flanking regions. Source data
Supplementary Note and Methods
Supplementary Tables 1–4
Example of measurement of the elasticity of a single isolated nucleus. This nucleus is not digested with a restriction enzyme. Example of measurement of the elasticity of a single isolated nucleus. This nucleus is digested with DpnII prior to measurement for 1 hour.
Example of measurement of the elasticity of a single isolated nucleus. This nucleus is digested with DpnII prior to measurement for 1 hour.
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Belaghzal, H., Borrman, T., Stephens, A.D. et al. Liquid chromatin Hi-C characterizes compartment-dependent chromatin interaction dynamics. Nat Genet (2021). https://doi.org/10.1038/s41588-021-00784-4