Genome reorganization and its functional impact during breast cancer progression
- National Cancer Institute, National Institutes of Health, United States
- Department of Biochemistry and University of Vermont Cancer Center, University of Vermont Larner College of Medicine, United States
- OMICS Technology Facility, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, United States
- College of Nursing and Health Sciences, University of Vermont Cancer Center, United States
Figures
Figure 1 with 4 supplements
Reorganization of compartments, topologically associating domains (TADs), and loops during breast cancer progression.
(A) A diagram of the experimental design. Three epithelial cell lines represent various stages of breast cancer progression; MCF10A are non-cancerous, MCF10AT1 are pre-malignant, and MCF10CA1a are metastatic. In each cell line, we generated 5-kb resolution Micro-C to identify features such as compartments, TADs, and chromatin loops. We overlapped these features with functional changes in gene expression from RNA-Seq, histone modifications, and CTCF binding from ChIP-Seq, and chromatin accessibility from ATAC-Seq. (B) Micro-C maps of a 2-Mb region of chromosome 1 in MCF10A (non-cancerous), MCF10AT1 (pre-cancerous), and MCF10CA1a (metastatic) cells at 5-kb resolution. Each map has annotations for loop calls, both static (black boxes) and differential (red boxes). Below each map is a track indicating compartment calls from CALDER (dark red is most A-like, dark blue is most B-like) as well as insulation scores tracks with static (gray) and differential (red) boundaries marked. Ribbons indicate TAD calls for each cell type. (C) Lengths of the genome assigned to each compartment in each cell type. (D) Numbers of TAD and (E) loop calls from each cell type, colored by the number of cell types in which they were initially detected . (F) Saddle plots of interactions between regions of different compartments in MCF10A, MCF10AT1, and MCF10CA1a. Bottom plots indicate the average eigenvector value for each compartment ventile. Plots shown are for chromosomes 2, 12, and 17 (see Methods). (G) Left: Differential TAD boundaries clustered by their timing of change, depicted in line plots and heatmap. Right: Aggregate plots of weakened and strengthened TAD boundaries (n = 100). (H) Left: Differential chromatin loops clustered by their timing of change, depicted in line plots and heatmap. Right: Aggregate plots of weakened and strengthened loops (n = 100).
Figure 1—figure supplement 1
Karyotypic analysis and Micro-C loop reproducibility.
(A) Brightfield microscopy images of MCF10A, MCF10AT1, and MCF10CA1a cell lines. (B) Representative SKY karyotype example images from MCF10A, MCF10AT1, and MCF10CA1a cell lines. (C) Copy number variation (CNV) factors for loops across the genome as generated from NeoloopFinder. Highlighted regions indicate areas of karyotypic differences that were corrected for in the identification of differential loops; blue is regions with higher CNV in MCF10A, yellow is regions with higher CNV in MCF10AT1, and red is regions with higher CNV in MCF10CA1a. Regions that have shared karyotypic abnormalities among all three cell lines, such as the q arm of chromosome 5 which is duplicated and translocated to chromosome 9 in all cell types, did not require correction. (D) Micro-C chromatin loop count principal component analysis (PCA). Blue circles indicate MCF10A samples, yellow circles indicate MCF10AT1, and red circles indicate MCF10CA1a.
Figure 1—figure supplement 2
Differential loop and topologically associating domain (TAD) feature details.
(A) The number of chromatin loops that exhibit a significant increase (blue) or decrease (green) in contact frequency between each pairwise comparison of cell types. (B) The number of TAD boundaries that exhibit a significant increase (blue) or decrease (green) in insulation score between each pairwise comparison of cell types. (C) Size distributions of chromatin loops and TADs. (D) Permutation test results of weakened boundaries observed in each pairwise comparison as compared to a random sampling. (E) Percent of loops with one or both anchors overlapping CTCF ChIP-Seq peaks based on the strength of the loop (20 bins). (F) Boxplots of (left to right) maximum loop Micro-C counts, maximum loop count log2 fold-change, and loop length based on loop-CTCF class; neither (gray), one anchor overlap (light red), or both anchors overlap (dark red). (G) Venn diagram showing the degree of overlap between chromatin loops and TADs. (H) Feature sizes of loops that do not overlap TADs (light gray), loops that do overlap TADs (dark gray), TADs that do overlap loops (dark blue), and TADs that do not overlap loops (light blue). (I) Pie chart of the percentage of differential loops that have a correlated change in CTCF binding at either anchor; light gray indicates static CTCF peaks, dark gray indicates CTCF peaks that change in the opposite way as the loop (i.e. a strengthened loop with loss of CTCF binding), and dark red indicates CTCF peaks that change in the same way as the loop (i.e. a strengthened loop with gain of CTCF binding). (J) De novo motif results from HOMER for ATAC-Seq peaks within the anchors of gained/strengthened (top) and lost/weakened (bottom) chromatin loops. (K) H3K27ac ChIP-Seq aggregate profiles at the anchors of gained/strengthened, lost/weakened, and static loops.
Figure 1—figure supplement 3
Differential MCF10 loops are conserved in cancer cell lines.
(A) Aggregate loop analysis of chromatin loops from each differential cluster as found in the MCF10 series compared to triple negative breast cancer (TNBC) cell lines and primary patient tissues (Kim et al., 2022). Red boxes indicate loops that have significantly higher observed/expected contact frequency among loops in that cluster as compared to a random sampling of an equal number of chromatin loops that are static in the MCF10 series, as determined in (B). (B) Boxplots representing quantifications of the aggregate plots shown in (A). Filled boxes indicate the counts from loops in each differential cluster, while empty boxes indicate a matched sample of static loops that are of similar size. Stars indicate cell lines where there is a significant difference between the counts of the given loops and the static matched set (P ≤ 0.05, Wilcoxon rank sum test).
Figure 1—figure supplement 4
Differential topologically associating domain (TAD) boundaries are conserved in cancer cell lines and tissues.
(A) Average insulation score profile of TAD boundaries based on their differential cluster in MCF10 progression and in triple negative breast cancer (TNBC) cell lines and primary patient tissues (Kim et al., 2022). (B) Boxplots showing the distribution of insulation scores at MCF10 boundaries of various differential clusters. Filled boxes indicate the insulation scores from TADs in each differential cluster, while empty boxes indicate the distribution of scores at the same number of static TAD boundaries. Stars indicate cell lines where there is a significant difference between the insulation score of boundaries and the static matched set (p ≤ 0.05, Wilcoxon rank sum test). (C) Aggregate plots showing the log2 of observed/expected counts at MCF10 boundaries in MCF10 cell lines as well as cell lines from Kim et al., 2022.
Figure 2 with 5 supplements
Persistent chromatin loops connect differentially expressed genes to distal enhancers.
(A) Percentages of loops designated as either promoter–promoter, enhancer–promoter, enhancer–enhancer, or single-sided promoter or enhancer loops. (B) Distributions of loop sizes by enhancer/promoter designations. p-values represent Wilcoxon tests comparing the means of different loop classes. Boxplots show the median (middle line), 25th and 75th quartiles (box perimeters), and range excluding outliers (dashed line whiskers). Outliers are defined as values that are over 1.5 times the interquartile range beyond the box bounds and are excluded from these plots. p-values represent Wilcoxon tests comparing the means of various loop sets. Non-significant (n.s.) represents p-values above 0.05. (C) Distributions of loop strength by enhancer/promoter designations. p-values represent Wilcoxon tests comparing the means of various loop sets. Non-significant (n.s.) represents p-values above 0.05. (D) Percentages of upregulated genes that have gained H3K27ac at promoters, distal enhancers, both, or gained loops. (E) Log2 fold-change of distal H3K27me3 (gray), distal H3K27ac (red), promoter H3K27ac (orange), gene expression (yellow), and loop strength (blue), when overlapped. Gray dots indicate features that do not change significantly, while colored points are significantly differential features. Boxplots are defined as in (B). p-values represent Wilcoxon tests comparing the means of each class to 0. Non-significant (n.s.) represents p-values above 0.01. (F) Percentages of downregulated genes that have gained H3K27ac at promoters, distal enhancers, both, or gained loops. (G) Log2 fold-change of distal H3K27me3 (gray), distal H3K27ac (red), promoter H3K27ac (orange), gene expression (yellow), and loop strength (blue), when overlapped. Boxplot details as defined in (E). (H) An example of an upregulated gene (SPRY1) connected to gained enhancers by static loops. Black boxes show loop annotations. Red compartment tracks indicate A compartments, while blue indicates B compartments. In CTCF signal tracks, red highlights indicate differential CTCF peaks. In H3K27ac and ATAC-Seq signal tracks, red highlights indicate differential enhancers as determined by changes in H3K27ac. Genes highlighted in black are differentially expressed. (I) An example of downregulated genes (SCNN1G and SCNN1B) connected to lost enhancers by static loops. Plot annotations are as described in (H).
Figure 2—figure supplement 1
Differential gene expression patterns across breast cancer progression include cancer-relevant pathways.
(A) The number of genes that exhibit a significant increase (orange) or decrease (gold) in expression between each pairwise comparison of cell types. (B) Differential genes clustered by their timing of change, depicted in line plots and heatmap. (C) Gene ontology (GO) term enrichment for genes differentially expressed in each pairwise comparison of cells. (D) Gene set enrichment analysis (GSEA) results showing gene sets enriched among genes differentially expressed early (MCF10AT1, top) or late (MCF10CA1a, bottom) in breast cancer progression. (E) A heatmap shows the expression of all differential genes in the MCF10 progression series among normal (gray) and tumor (gold) tissue samples from the Cancer Genome Atlas breast cancer cohort. Genes are clustered first by their pattern of change in MCF10, then their differential status in the patient data. Example genes used in the study are listed on the right. Each cluster also shows a pie chart on the left depicting the percent of genes that are shared in the patient data, with genes that change in the same direction highlighted.
Figure 2—figure supplement 2
Clinical relevance of select genes misregulated in MCF10.
Overall survival curves from the Cancer Genome Atlas for fourteen select genes highlighted in the main figures (A), Figure 4—figure supplement 2 (B, C), and Figure 2—figure supplement 3 (D). (E) Gene expression data from the Cancer Genome Atlas for fourteen select genes. Gray boxplots represent expression values from normal samples and gold represent tumor samples. p-values represent the Wilcoxon rank-sum test comparing the normal and tumor expression levels for each gene.
Figure 2—figure supplement 3
Differentially expressed genes overlap differential and static loops with differential distal regulatory regions.
(A) The number of promoter H3K27ac peaks (left), distal enhancer H3K27ac peaks (middle), or loops (right) that change in a positive (gray) or negative (gold, red, blue) direction based on their overlap with up- or downregulated genes. (B) Same plots as (E) but subset for significantly differential features. (C–F) Examples of genes that are differentially regulated in the same direction in MCF10 progression and patient samples and which overlap with chromatin loops in MCF10 cell lines. Black boxes show loop annotations, while red boxes indicate differential loops. Red compartment tracks indicate A compartments, while blue indicates B compartments. In CTCF signal tracks, red highlights indicate differential CTCF peaks. In H3K27ac and ATAC-Seq signal tracks, red highlights indicate differential enhancers as determined by changes in H3K27ac. Genes highlighted in black are differentially expressed.
Figure 2—figure supplement 4
Relationship between differential gene expression, chromatin loops, and distal enhancers is consistent based on expression levels and cancer stages.
(A) Percentage of genes that overlap with loop anchors based on gene expression level. (B) Percentages of off-to-on genes that have gained H3K27ac at promoters, distal enhancers, both, or gained loops. (C) Log2 fold-change of distal H3K27me3 (gray), distal H3K27ac (red), promoter H3K27ac (orange), gene expression (yellow), and loop strength (blue), when overlapped. Gray dots indicate features that do not change significantly, while colored points are significantly differential features. p-values represent Wilcoxon tests comparing the means of each class to 0. Non-significant (n.s.) represents p-values above 0.01. (D–I) Same as (B, C), but for on-to-off genes (D, E), on-to-high genes (F, G), and high-to-on genes (H, I). (J) Percentages of upregulated genes (left) and downregulated genes (right) that have correlated changes in H3K27ac at promoters (gold), distal enhancers (red), both (orange), or loop contact frequency (blue), by pairwise comparison of cell types.
Figure 2—figure supplement 5
Differential topologically associating domain (TAD) boundaries and subcompartment shifts have a subtle relationship to gene expression.
(A) Pie charts showing the differential status of genes within 50 kb of TAD boundaries of various differential clusters. (B) Boxplots of the log2 fold-change of genes at the boundaries of TAD boundaries that are either weakened (blue), strengthened (green), or static (gray). p-values represent Wilcoxon rank sum tests comparing the mean of each set to the static set. (C) Alluvial plots showing the transition of subcompartments from MCF10A to MCF10AT1 and from MCF10AT1 to MCF10CA1a. Gray ribbons indicate bins that have the same subcompartments between cell types, while red ribbons shift more A-like and blue ribbons shift more B-like. Darker ribbons shift by more than one subcompartment. A pie chart to the right summarizes how many subcompartments all bins shift by, with negative numbers (blue) indicating shifts towards more B-like compartments and positive numbers (red) indicating shifts towards more A-like compartments. Alluvial plot showing the difference in subcompartments for the promoters of (D) actively expressed or (E) non-expressed genes that have similar gene expression in MCF10A and MCF10CA1a. Plots and pie charts are colored as in (C). Alluvial plots showing the difference in subcompartments for the promoters of genes that are differentially expressed between any two cell types (F), change from on to off (G), or change from on to high (H). For each figure, the left bar shows the subcompartments in the cell line with lower expression and the right bar is from the cell line with higher expression. The pie charts summarize the shifts as in (C). (I) A boxplot indicating the distribution of gene log2 fold-change between MCF10A and MCF10CA1a for genes with promoters in bins that shift by various numbers of subcompartments. Negative numbers (blue) indicate bins that shift to more B-like subcompartments, while positive numbers (red) indicate shifts to more A-like subcompartments. The numbers below indicate the number of bins that fit into each category. Stars indicate significant differences in mean gene log2 fold-change compared to genes that do not change subcompartments between the two cell types (gray), as indicated by a p-value of 0.01 or less (Wilcoxon rank sum test).
Figure 3 with 1 supplement
Changes in enhancer acetylation or enhancer–promoter contact are associated with changes in gene expression.
Boxplots of distal enhancer H3K27ac (pink), enhancer–promoter contact (blue), and activity-by-contact (ABC) score (purple), as well as gene log2 fold-change (yellow) for enhancer promoter pairs that feature (A) differential H3K27ac among enhancers, (B) differential enhancer–promoter contact frequency, and (C) differential H3K27ac for enhancer–promoter pairs supported by a chromatin loop. Boxplots in (D) and (E) represent sets of non-looped enhancer–promoter pairs with differential H3K27ac that are matched to the looped set in (C) by contact and distance, respectively. Boxplots show the median (middle line), 25th and 75th quartiles (box perimeters), and range excluding outliers (dashed line whiskers). Outliers are defined as values that are over 1.5 times the interquartile range beyond the box bounds and are excluded from these plots. p-values represent T-tests comparing the means of values in MCF10A and MCF10CA1a for enhancer activity, enhancer–promoter contact, and ABC score, and T-tests comparing the mean of the value to 0 for gene log2 fold-change. (F) Contact distribution of all enhancer–promoter pairs (dashed line), compared to the looped enhancer–promoter pairs in (C, solid line), the contact-matched pairs in (D, blue shade), and the distance-matched pairs in (E, gray shade). (F) Distance distribution of all enhancer–promoter pairs (dashed line), compared to the looped enhancer–promoter pairs in (C, solid line), the contact-matched pairs in (D, blue shade), and the distance-matched pairs in (E, gray shade). (G) Summary boxplot of the gene log2 fold-change for the enhancer–promoter pairs previously shown in figures (A–E). p-values represent T-tests comparing the means of average gene log2 fold-changes values for different sets of enhancer–promoter pairs.
Figure 3—figure supplement 1
Enhancer–promoter pair details.
(A) Distribution of enhancer–promoter distances as predicted by the activity-by-contact (ABC) model. (B) Boxplots of distal enhancer H3K27ac (pink), enhancer–promoter contact (blue), and ABC score (purple), as well as gene log2 fold-change (yellow) for enhancer promoter pairs that feature (top to bottom) differential H3K27ac among enhancers, differential enhancer–promoter contact frequency, differential H3K27ac for looped enhancer–promoter pairs, contact-matched non-looped enhancer–promoter pairs, and distance-matched non-looped enhancer–promoter pairs. Comparison shows changes between MCF10A and MCF10AT1. (C) Same as (B) but showing comparisons between MCF10AT1 and MCF10Ca1a.
Figure 4 with 2 supplements
Differential loops are enriched for cancer-relevant differentially expressed genes.
(A) Log2 fold-change of differentially expressed genes at the anchors of gained (blue), weakened (green), or static (gray) loops. Boxplots show the median (middle line), 25th and 75th quartiles (box perimeters), and range excluding outliers (dashed line whiskers). Outliers are defined as values that are over 1.5 times the interquartile range beyond the box bounds and are excluded from these plots. p-values represent Wilcoxon tests comparing the mean of each set to 0. (B) Bar plot showing the number of differentially expressed genes at strengthened or weakened loop anchors. Bar segments are colored by whether the gene is changing the same (blue for upregulated in strengthened loops, green for downregulated in weakened loops) or opposite (gray) direction as the loop. p-value represents a Fisher’s exact test for whether the odds ratio (OR) is greater than 1. (C) Gene ontology (GO) term enrichments for genes upregulated in MCF10A, MCF10AT1, or MCF10CA1a. Size indicates p-value. Terms are color-coded based on gene type; morphogenesis (purple), proliferation (orange), and cell adhesion (teal). (D) An example of an upregulated gene (COL12A1) with a promoter that overlaps a strengthened loop with distal enhancers. Black boxes show loop annotations, while red boxes indicate differential loops. Red compartment tracks indicate A compartments, while blue indicates B compartments. In CTCF signal tracks, red highlights indicate differential CTCF peaks. In H3K27ac and ATAC-Seq signal tracks, red highlights indicate differential enhancers as determined by changes in H3K27ac. Genes highlighted in black are differentially expressed. (E) An example of a downregulated gene (WNT5A) with a promoter that overlaps with several weakened loops containing distal enhancers that lose H3K27ac. Plots are annotated as in (A).
Figure 4—figure supplement 1
Differential genes within differential loops.
(A) The number of differentially expressed genes among all genes (dashed light gray line), genes overlapping static loop anchors (dashed dark gray line), genes overlapping differential loop anchors (red line), and a permutation test of a random sampling of a similar number of genes (black line). (B) Permutation test results (n = 1000) for the number of upregulated genes that overlap with strengthened/gained loops (red) compared to a random sampling (black). (C) Permutation test results (n = 1000) for the number of downregulated genes that overlap with weakened/lost loops (red) compared to a random sampling (black). Boxplots in (D) and (E) represent log2 fold-change between MCF10A and MCF10AT1 (D) or MCF10AT1 and MCF10CA1a (E) of distal H3K27me3 (gray), distal H3K27ac (red), promoter H3K27ac (orange), gene expression (yellow), and loops (blue) among upregulated or downregulated genes that overlap with gained loops (darker colors) or lost loops (lighter colors). Boxplots are defined as in (A). p-values represent T-tests comparing the mean values of the features at loops that change in the same and those that change in opposite directions from the differential genes at their anchors. Non-significant (n.s.) p-values are any p-values above 0.01.
Figure 4—figure supplement 2
Examples of differentially expressed genes at differential loop anchors.
(A–C) Examples of genes that are differentially expressed in MCF10 progression and overlap with anchors of differential genes that change in the same direction. Black boxes show loop annotations, while red boxes indicate differential loops. Red compartment tracks indicate A compartments, while blue indicates B compartments. In CTCF signal tracks, red highlights indicate differential CTCF peaks. In H3K27ac and ATAC-Seq signal tracks, red highlights indicate differential enhancers as determined by changes in H3K27ac. Genes highlighted in black are differentially expressed. (D–F) Examples of genes that are differentially regulated in MCF10 progression and overlap with anchors of differential genes that change in the opposite direction. Plots are annotated as in (A–C).
Figure 5
Progression-associated differentially expressed genes exhibit local and distal epigenetic changes at differential loops.
Log2 fold-change of genes (colored dots) and the differential loops they overlap with (black/gray dots) for genes and loops that change between (A) MCF10A and MCF10AT1, (B) MCF10AT1 and MCF10CA1a, and (C) MCF10A and MCF10CA1a. Gene labels are below. (D) Log2 fold-change between MCF10A and MCF10CA1a of distal H3K27me3 (gray), distal H3K27ac (red), promoter H3K27ac (orange), gene expression (yellow), and loops (blue) among upregulated genes that overlap with gained loops (darker colors) or lost loops (lighter colors). Boxplots are defined as in (A). p-values represent T-tests comparing the mean values of the features at loops that change in the same and those that change in opposite directions from the differential genes at their anchors. Non-significant (n.s.) p-values are any p-values above 0.01. (E) Log2 fold-change of distal H3K27me3 (gray), distal H3K27ac (red), promoter H3K27ac (orange), gene expression (yellow), and loops (blue) among downregulated genes that overlap with gained loops (darker colors) or lost loops (lighter colors). p-values represent T-tests comparing the mean values of the features at loops that change in the same and those that change in opposite directions from the differential genes at their anchors. Non-significant (n.s.) p-values are any p-values above 0.01.
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Cell line (Homo sapiens) | Cell line MCF10A | ATCC | Cat#:CRL-10317; RRID:CVCL_0598 | Non-cancerous mammary epithelial cells |
| Cell line (Homo sapiens) | Cell line MCF10AT1 | Karmanos Cancer Institute | ID:MCF10AneoT; RRID:CVCL_5554 | Pre-malignant mammary epithelial cells |
| Cell line (Homo sapiens) | Cell line MCF10CA1a | Karmanos Cancer Institute | ID:MCF10CA1a.cl1; RRID:CVCL_6676 | Metastatic mammary epithelial cells |
| Antibody | anti-human CTCF (rabbit monoclonal) | Cell Signaling Technology | Cat#:3418 | ChIP-Seq (20 µl per 150 µg chromatin) |
| Antibody | anti-human H3K27ac (rabbit polyclonal) | AbCam | Cat#:ab4729; RRID:AB_2118291 | ChIP-Seq (2 µg per 10 µg chromatin) |
| Antibody | anti-human H3K27me3 (mouse monoclonal) | AbCam | Cat#:ab6002; RRID:AB_305237 | ChIP-Seq (4 µg per 15 µg chromatin) |
| Commercial assay or kit | Dovetail Micro-C Kit & Assay Service | Dovetail Genomics | Cat#:20101E | Loop level project |
| Commercial assay or kit | Direct-zol RNA Miniprep | Zymo Research | Cat#:R2050 | |
| Commercial assay or kit | NEBNext rRNA Depletion Kit v2 | New England Biolabs | Cat#:7400 | |
| Commercial assay or kit | NEBNext Ultra II RNA-Seq Library Prep Kit | New England Biolabs | Cat#:E7770 | |
| Software, algorithm | BWA mem | PMID:19451168 | RRID:SCR_010910 | Version 0.7.17 |
| Software, algorithm | Pairtools | https://doi.org/10.1101/2023.02.13.528389 | RRID:SCR_023038 | Version 0.3.0 |
| Software, algorithm | samtools | PMID:33590861 | RRID:SCR_002105 | Version 1.17 |
| Software, algorithm | Juicer tools | PMID:27467249 | RRID:SCR_017226 | Version 1.22.01 |
| Software, algorithm | NeoLoopFinder | PMID:34092790 | ||
| Software, algorithm | CALDER | PMID:33972523 | Version 2.0 | |
| Software, algorithm | FAN-C | PMID:33334380 | Version 0.9.21 | |
| Software, algorithm | SpectralTAD | PMID:32689928 | Version 1.18.0 | |
| Software, algorithm | SIP | PMID:32127418 | Version 1.6.2 | |
| Software, algorithm | STAR | PMID:23104886 | RRID:SCR_004463 | Version 2.4 |
| Software, algorithm | Trim Galore | https://doi.org/10.5281/zenodo.5127898 | RRID:SCR_011847 | |
| Software, algorithm | Bowtie2 | PMID:22388286 | RRID:SCR_016368 | |
| Software, algorithm | MACS2 | PMID:18798982 | RRID:SCR_013291 | |
| Software, algorithm | DESeq2 | PMID:25516281 | RRID:SCR_015687 | Version 1.42.0 |
| Software, algorithm | CSAW | PMID:26578583 | RRID:SCR_026738 | |
| Software, algorithm | GEPIA | PMID:40396370 | RRID:SCR_028242 | |
| Software, algorithm | GenomicRanges | PMID:23950696 | RRID:SCR_000025 | |
| Software, algorithm | mariner | PMID:38814811 | ||
| Software, algorithm | plotgardener | PMID:35134826 | ||
| Software, algorithm | Activity-by-contact | PMID:31784727 | ||
| Software, algorithm | nullranges | PMID:37084270 | ||
| Software, algorithm | GSEA | PMID:16199517 | RRID:SCR_003199 | |
| Software, algorithm | HOMER | PMID:20513432 | RRID:SCR_010881 |
Additional files
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Supplementary file 1
Micro-C library quality metrics for individual technical replicates, biological replicates, and cell types.
- https://cdn.elifesciences.org/articles/108135/elife-108135-supp1-v1.xlsx
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Supplementary file 2
CNVs from NeoLoopFinder (100-kb resolution).
Columns indicate bin coordinates (A–C), and CNV values for MCF10A (D), MCF10AT1 (E), and MCF10CA1a (F).
- https://cdn.elifesciences.org/articles/108135/elife-108135-supp2-v1.xlsx
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Supplementary file 3
Chromatin loop summary table for total loop set (n = 29,205).
Columns include loop anchor coordinates (A–J), loop call status by cell type (K–N), SIP AP score (O), loop name (P), loop span length (Q), average and maximum unnormalized counts (R–S), log2 fold-change (T–V), adjusted p-value (W), differential status by pairwise comparison (X–Z), unnormalized counts by technical replicate (AA–AX), maximum log2 fold-change (AY), pairwise comparison with greatest fold-change (AZ), differential cluster (BA), Z-score normalized counts (BB–BE), and variance stabilized counts (BF–BH).
- https://cdn.elifesciences.org/articles/108135/elife-108135-supp3-v1.xlsx
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Supplementary file 4
TAD boundary summary table for total boundary set (n = 17,097).
Columns include boundary coordinates (A–C), insulation scores by technical replicate (D–AA), adjusted p-values, difference in insulation score, and differential status for each pairwise comparison (AB–AJ), differential status across all comparisons (AK), differential cluster (AL), average insulation score per cell type (AM–AO), and Z-score normalized insulation scores (AP–AS).
- https://cdn.elifesciences.org/articles/108135/elife-108135-supp4-v1.xlsx
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Supplementary file 5
TAD summary table for total set of TADs (n = 13,231).
Columns include TAD boundary coordinates (A–J), and whether the TAD was called in each cell type (K–M).
- https://cdn.elifesciences.org/articles/108135/elife-108135-supp5-v1.xlsx
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Supplementary file 6
Differentially expressed genes from the MCF10 progression series (n = 8840).
Columns indicate gene coordinates (A–E), gene identifiers (F–I), base mean expression (J), pairwise log2 fold-change (K–M), adjusted p-values (N–P), and differential status (Q–S), differential cluster (T), unnormalized counts by replicate (U–AC), Z-score normalized counts (AD–AF), and variance stabilized counts (AG–AI).
- https://cdn.elifesciences.org/articles/108135/elife-108135-supp6-v1.xlsx
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MDAR checklist
- https://cdn.elifesciences.org/articles/108135/elife-108135-mdarchecklist1-v1.pdf
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Genome reorganization and its functional impact during breast cancer progression
eLife 14:RP108135.
https://doi.org/10.7554/eLife.108135.3
