Joint annotation of chromatin state and chromatin conformation reveals relationships among domain types and identifies domains of cell-type-specific expression
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Abstract
The genomic neighborhood of a gene influences its activity, a behavior that is attributable in part to domain-scale regulation. Previous genomic studies have identified many types of regulatory domains. However, due to the difficulty of integrating genomics data sets, the relationships among these domain types are poorly understood. Semi-automated genome annotation (SAGA) algorithms facilitate human interpretation of heterogeneous collections of genomics data by simultaneously partitioning the human genome and assigning labels to the resulting genomic segments. However, existing SAGA methods cannot integrate inherently pairwise chromatin conformation data. We developed a new computational method, called graph-based regularization (GBR), for expressing a pairwise prior that encourages certain pairs of genomic loci to receive the same label in a genome annotation. We used GBR to exploit chromatin conformation information during genome annotation by encouraging positions that are close in 3D to occupy the same type of domain. Using this approach, we produced a model of chromatin domains in eight human cell types, thereby revealing the relationships among known domain types. Through this model, we identified clusters of tightly regulated genes expressed in only a small number of cell types, which we term “specific expression domains.” We found that domain boundaries marked by promoters and CTCF motifs are consistent between cell types even when domain activity changes. Finally, we showed that GBR can be used to transfer information from well-studied cell types to less well-characterized cell types during genome annotation, making it possible to produce high-quality annotations of the hundreds of cell types with limited available data.
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Five distinct groups of TADs were identified by k-means clustering of chromatin state coverage: heterochromatin (61), low/quiescent (705), repressed (481), low-active (764) and active (365) domains.
“The obtained matrix was grouped using the k-means clustering approach and five distinct groups of TADs were identified similar to a previous classification of chromatin domains17,19,33. These groups comprised heterochromatin (61), low/quiescent (705), repressed (481), low-active (764) and active (365) domains (Fig. 4a, Supplementary Table 4).”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [33]
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Additional file 3 of SPIN reveals genome-wide landscape of nuclear compartmentalization
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Self-citationAdditional file 4 of SPIN reveals genome-wide landscape of nuclear compartmentalization
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Miko, H., Qiu, Y., Gaertner, B., Sander, M., & Ohler, U. (2021) · Figshare · doi:10.6084/m9.figshare.13662642
Additional file 6 of SPIN reveals genome-wide landscape of nuclear compartmentalization
Wang, Y., Zhang, Y., Zhang, R., van Schaik, T., Zhang, L., Sasaki, T., Peric‐Hupkes, D., Chen, Y., Gilbert, D. M., van Steensel, B., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13579170
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Fang, K., Li, T., Huang, Y., & Jin, V. X. (2021) · Figshare · doi:10.6084/m9.figshare.16456278
Additional file 2 of SPIN reveals genome-wide landscape of nuclear compartmentalization
Wang, Y., Zhang, Y., Zhang, R., van Schaik, T., Zhang, L., Sasaki, T., Peric‐Hupkes, D., Chen, Y., Gilbert, D. M., van Steensel, B., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13579158
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Miko, H., Qiu, Y., Gaertner, B., Sander, M., & Ohler, U. (2021) · Figshare · doi:10.6084/m9.figshare.13662636
Additional file 1 of SPIN reveals genome-wide landscape of nuclear compartmentalization
Wang, Y., Zhang, Y., Zhang, R., van Schaik, T., Zhang, L., Sasaki, T., Peric‐Hupkes, D., Chen, Y., Gilbert, D. M., van Steensel, B., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13579155
Self-citationFang, K., Li, T., Huang, Y., & Jin, V. X. (2021) · Figshare · doi:10.6084/m9.figshare.16456263
- Authors
- Libbrecht, M. W., Ay, F., Hoffman, M. M., Gilbert, D. M., Bilmes, J. A., & Noble, W. S.
- Affiliations
- University of Washington (US)
- University of Toronto (CA)
- Florida State University (US)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2015-02-12
- Volume
- 25
- Issue
- 4
- Pages
- 544-557
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC4381526
- OpenAlex
- W2146339031
- Cited by
- 84
- References
- 67
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 3 · 2022: 8 · 2021: 22 · 2020: 5 · 2019: 7 · 2018: 9 · 2017: 6 · 2016: 11 · 2015: 7 · 2014: 1
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- NIH (U41HG007000, R01ES024917)
- 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 › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- chromatin domains, chromatin conformation, 3D genome organization, graph regularization, cell type-specific gene expression, domain boundaries, promoter, regulatory domain
- MeSH terms
- Algorithms, Chromatin, HeLa Cells, Humans, Molecular Conformation, Promoter Regions, Genetic, Genome, Human, Computational Biology, Amino Acid Motifs, Chromosome Structures, Genomics, Cell Line, Tumor, Hep G2 Cells, Molecular Sequence Annotation, Human Umbilical Vein Endothelial Cells
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