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Accurate prediction of cohesin-mediated 3D genome organization from 2D chromatin features
Open accessPreprint — published as 10.1186/s13059-023-03158-7 · Paper page
Abstract
The three-dimensional (3D) genome organization influences diverse nuclear processes. Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) and Hi-C are powerful methods to study the 3D genome organization. However, ChIA-PET and Hi-C experiments are expensive, time-consuming, require tens to hundreds of millions of cells, and are challenging to optimize and analyze. Predicting ChIA-PET/Hi-C data using cheaper ChIP-Seq data and other easily obtainable features could be a useful alternative. It is well-established that the cohesin protein complex is a key determinant of 3D genome organization. Here we present Chromatin Interaction Predictor (ChIPr), a suite of regression models based on deep neural networks (DNN), random forest, and gradient boosting, respectively, to predict cohesin-mediated chromatin interaction strength between any two loci in the genome. Comprehensive tests on four cell lines show that the predictions of ChIPr correlate well with the original ChIA-PET data at the peak-level resolution and bin sizes of 25 and 5 Kbp. In addition, ChIPr can accurately capture most of the cell-type-dependent loops identified by ChIA-PET and Hi-C data. Rigorous feature testing indicated that genomic distance and RAD21 (a cohesin component) ChIP-Seq signals are the most important inputs for ChIPr in determining chromatin interaction strength. The standard ChIPr model requires three experimental inputs: ChIP-Seq signals for RAD21, H3K27ac (enhancer/active chromatin mark) and H3K27me3 (inactive chromatin mark). The minimal ChIPr model performs comparably and requires a single experimental input: ChIP-Seq signals for RAD21. Integrative analysis revealed novel insights into the role of CTCF motif, its orientation, and CTCF binding on the prevalence and strength of cohesin-mediated chromatin interactions. These studies outline the general features of genome folding and open new avenues to analyze spatial genome organization in specimens with limited cell numbers.
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![Fig. 12 ChIPr outperforms other 3D chromatin prediction methods. A The RAD21 25 kbp contact maps predicted by the three variants of ChIPr yield significantly higher SCC values when compared with the original contact maps than those yielded by 3Dpredictor contact maps. B The 25 kbp Hi-C contact maps predicted by the three variants of ChIPr yield significantly higher SCC values when compared with the original contact maps than those yielded by 3Dpredictor contact maps. C, D The original contact map of an 8 Mbp region in Chr9 (C) looks visually similar to its corresponding GB-ChIPr (D) prediction. E The predictions of the three variants of ChIPr, using the models trained on the IMR90 cell line data, correlate significantly better than control interactions when compared with the original Hi-C interactions for the two cell lines GM12878 and K562. F The predictions of the three variants of ChIPr, using the models trained on K562 and IMR90 cell line data, yield significantly higher Pearson correlation coefficient values than those obtained by C.Origami when comparing the 8 kbp resolution contact maps with the corresponding original ones for 23 randomly selected 2Mbp regions. G The predictions of the three variants of ChIPr, using the models trained on the H1 cell line Micro-C data (Chr1 only), correlate significantly better than control interactions when compared with the original Micro-C interactions for the remaining 22 chromosomes. H The three variants of ChIPr yield significantly higher Pearson correlation coefficient values when comparing the 5 kbp resolution observed contact maps with the original contact maps than those yielded by Orca 4 kbp contact maps for 16 selected regions in Chrs 8, 9, and 10. ****: p-value < 0.0001, Wilcoxon rank sum test. For SCC calculations in A, B, we set the smoothing window half-size h to “2” and the maximum genomic distance to include in calculations to 1.5 Mbp as used in 3Dpredictor paper. For C, D, visualization of contact maps is done using HiCPlotter [37]](/paper-figures/84905bf13a104327be65f90d2498b67d/accurate-prediction-of-cohesin-mediated-3d-genome-organization-from-2d-chromatin-figure-12.jpg)
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Metadata
- Authors
- Abbas, A., Chandratre, K., Gao, Y., Yuan, J., Zhang, M. Q., & Mani, R. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- The University of Texas at Dallas (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Zhang, Michael Q.
- Mani, Ram S.
- Venue
- Genome biology
- Publisher
- openRxiv
- Published
- 2022-11-25
- Volume
- 25
- Issue
- 1
- Pages
- 15-15
- ISSN
- 1465-6906 (ISSN-L)
- PMC
- PMC10785520
- OpenAlex
- W4390790903
- Cited by
- 13
- References
- 1
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Genome biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense (W81XWH, W81XWH2110114)
- Cancer Prevention and Research Institute of Texas (RP230382)
- University of Texas Southwestern Medical Center
- National Institutes of Health (W81XWH)
- National Cancer Institute (R01CA245294)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Keywords
- 3D genome organization, RAD21, H3K27ac, H3K27me3, CTCF binding, chromatin interaction prediction, deep neural network, gradient boosting, random forest, ChIA-PET
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Chromatin, Chromosomal Proteins, Non-Histone, Cell Cycle Proteins
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