Two independent modes of chromatin organization revealed by cohesin removal
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Abstract
Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-sized active and inactive compartments, and partitioning into sub-megabase domains (TADs). It remains unclear, however, how these layers of organization form, interact with one another and influence genome function. Here we show that deletion of the cohesin-loading factor Nipbl in mouse liver leads to a marked reorganization of chromosomal folding. TADs and associated Hi-C peaks vanish globally, even in the absence of transcriptional changes. By contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the three-dimensional organization of the genome results from the interplay of two independent mechanisms: cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; and cohesin-dependent formation of TADs, possibly by loop extrusion, which helps to guide distant enhancers to their target genes.
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Deletion or degradation of cohesin or CTCF in differentiated cells has only mild effects on gene expression.
“Surprisingly however, deletion or degradation of cohesin or CTCF in differentiated cells has only mild effects on gene expression [344–349].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [348]
In “Transcriptional changes upon TAD loss” (page unavailable), the paper reports that Nipbl deletion in differentiated hepatocytes significantly altered expression of about a thousand genes, while the cells’ regulatory potential was mostly unperturbed. This supports a limited overall effect, but the paper does not establish that the expression changes were uniformly mild or report gene-expression effects from CTCF deletion or degradation. (LLM, conf=0.83)
Experimental — accuracy not yet measuredA/B compartment structure does not disappear (and is in fact even strengthened) upon cohesin/CTCF depletion, but, like TADs, dissolves in mitosis.
“The A/B compartment structure does not disappear (and is in fact even strengthened) upon cohesin/CTCF depletion [344, 346–348], but, like TADs, dissolves in mitosis [459].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [348]
In “Enhanced and finer compartmentalization” (page unavailable), the paper reports that A/B compartmentalization persists and is enhanced about 1.8-fold after Nipbl deletion, supporting the cohesin-depletion part of the cited clause. It does not report strengthened A/B compartments after CTCF depletion. The mitosis clause carries a separate citation and is not assessed here. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPolymer simulation studies and Hi-C studies employing acute depletion of CTCF and cohesin support a dynamic model of TADs and chromatin loops.
“complementary polymer simulation studies and Hi-C studies employing acute depletion of CTCF and cohesin, which also support such a dynamic model.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [11]
Since multiple studies show that TADs and chromatin loops disappear without CTCF and cohesin, the most stable protein of CTCF and cohesin should set an upper limit on the stability of TADs and chromatin loops.
“Since multiple studies show that TADs and chromatin loops disappear without CTCF10,14 and cohesin,11,13–15 we reasoned that the most stable protein of CTCF and cohesin should set an upper limit on the stability of TADs and chromatin loops.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [11]
Cohesin loss leads to disappearance of TADs because extrusion no longer takes place.
“In contrast, cohesin loss leads to disappearance of TADs because extrusion no longer takes place.11,13–15”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [11]
CTCF and cohesin both appear absolutely required for the formation of most TADs.
“although CTCF and cohesin both appear absolutely required for the formation of most TADs10-15”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [11]
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Self-citation
- Authors
- Schwarzer, W., Abdennur, N., Goloborodko, A., Pekowska, A., Fudenberg, G., Loe-Mie, Y., Fonseca, N. A., Huber, W., Haering, C. H., Mirny, L., & Spitz, F.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Massachusetts Institute of Technology (US)
- Centre National de la Recherche Scientifique (FR)
- European Bioinformatics Institute (GB)
- Corresponding author
- Mirny, Leonid
- ORCID
- Venue
- Nature
- Published
- 2017-09-27
- Volume
- 551
- Issue
- 7678
- Pages
- 51-56
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5687303
- OpenAlex
- W2757387674
- Cited by
- 1,196
- References
- 78
- Citations by year
- 2026: 83 · 2025: 121 · 2024: 114 · 2023: 120 · 2022: 142 · 2021: 158 · 2020: 153 · 2019: 159 · 2018: 113 · 2017: 32 · 2016: 1
- FWCI
- 51.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Science Foundation (1504942)
- European Molecular Biology Laboratory
- European Commission (305626)
- Deutsche Forschungsgemeinschaft (1331/3-1, SP 1331/3-1)
- National Institutes of Health (DK 107980)
- National Institute of General Medical Sciences (R01GM114190)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK107980)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- chromatin organization, topologically associating domains, cohesin, NIPBL, loop extrusion, enhancer-promoter interactions, 3D genome organization, chromatin state, CTCF, interphase chromosomes, hepatocytes, genome compartmentalization
- MeSH terms
- Cohesins, Animals, Chromatin, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Liver, Transcription Factors, Transcription, Genetic, Cell Cycle Proteins, Epigenesis, Genetic, Chromosome Positioning, Mice
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