Architectural protein subclasses shape 3D organization of genomes during lineage commitment
Open accessAbstract
Understanding the topological configurations of chromatin may reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here, we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3D interactions that undergo marked reorganization at the submegabase scale during differentiation. Distinct combinations of CCCTC-binding factor (CTCF), Mediator, and cohesin show widespread enrichment in chromatin interactions at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant subdomains. Conversely, Mediator/cohesin bridge short-range enhancer-promoter interactions within and between larger subdomains. Knockdown of Smc1 or Med12 in embryonic stem cells results in disruption of spatial architecture and downregulation of genes found in cohesin-mediated interactions. We conclude that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales.
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The Sox2 gene has an essential enhancer, the Sox2 Control Region (SCR), which was found by 3C-derived techniques to loop to the Sox2 promoter.
“The Sox2 gene has an essential enhancer, the Sox2 Control Region (SCR), which was found by 3C-derived techniques to loop to the Sox2 promoter (for example, [379, 401]).”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [379]
In Results, “Constitutive and cell type-specific features of 3-D chromatin organization” (page unavailable), the paper reports that 5C data show looping interactions between Sox2 and a putative downstream enhancer in ES cells. It does not identify that enhancer as the Sox2 Control Region (SCR) or establish that it is essential. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe cohesin complex is an important architectural protein that organizes the 3D genome and is also important in DSB repair.
“The cohesin complex is an important architectural protein that organizes the 3D genome and is also important in DSB repair”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [76]
Interaction scores have proven to be informatively comparable across replicates and conditions.
“Interaction scores have proven to be informatively comparable across replicates and conditions21”
From Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression (2020) · cites this paper as [21]
CTCF/Cohesin sites dispersed within TADs are thought to contribute to the formation of smaller self-interacting domains termed sub-TADs, contact domains, and insulated neighborhoods.
“These CTCF/Cohesin sites are thought to contribute to the formation of smaller self-interacting domains that have been termed sub-TADs18, contact domains19, and insulated neighborhoods11,20.”
From Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (2017) · cites this paper as [18]
There is enrichment for CTCF at human ES cell boundaries compared to loci internal to domains.
“Consistent with previous reports, we found enrichment for the architectural protein CCCTC-binding factor (CTCF) at human ES cell boundaries compared to loci internal to domains (Figure S6A-B) (Dixon et al., 2012; Nora et al., 2012; Phillips-Cremins et al., 2013).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Phillips-Cremins et al., 2013
Architectural proteins such as CTCF and cohesin play a role in domain formation.
“It is known that architectural proteins such as CTCF and cohesin play a role (Haarhuis et al., 2017, Nora et al., 2017, Phillips-Cremins et al., 2013)”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Phillips-Cremins et al., 2013
Chromatin insulation occurs at multiple levels and leads to a hierarchical 3D nuclear organization, whereby smaller, less insulated regions (sub-TADs/contact domains) are nested inside TADs.
“Chromatin insulation occurs at multiple levels and leads to a hierarchical 3D nuclear organization, whereby smaller, less insulated regions (called also sub-TADs [Flavahan et al., 2016, Phillips-Cremins et al., 2013] or contact domains [Rao et al., 2014]) are nested inside TADs, which are usually bigger and more strongly insulated (Dixon et al., 2012, Nora et al., 2012, Sexton et al., 2012).”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Phillips-Cremins et al., 2013
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BackgroundResultInfluentialCohesin is positioned in mammalian genomes by transcription, CTCF and Wapl
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The Genetics of Transcription Factor DNA Binding Variation
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The 3D genome in transcriptional regulation and pluripotency
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Wapl is an essential regulator of chromatin structure and chromosome segregation
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Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control
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Cohesin-mediated interactions organize chromosomal domain architecture
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“We and others have previously re-ported that pluripotency genes connect to enhancers in smaller looping interactions nested within larger constitutive structures (Phillips-Cremins et al. 2013; Dowen et al. 2014).”
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Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries
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“Paired-end reads were mapped to a pseudo-reference genome representing all possible 5C primer ligation junctions as previously described (Beagan et al., 2016, 2016; Phillips-Cremins et al., 2013) (Table S6B).”
Self-citationDynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation
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Cell-of-origin-specific 3D genome structure acquired during somatic cell reprogramming
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Reorganization of chromosome architecture in replicative cellular senescence
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“…studies provided evidence of interactions associated with transcriptional changes upon line- age commitment (Denholtz et al., 2013; Kieffer-Kwon et al., 2013; Phillips-Cremins et al., 2013; eLife digest Virtually every cell in the body contains the same set of DNA, which encodes thousands of genes.”
BackgroundResultDetecting hierarchical genome folding with network modularity
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Self-citationLADL: light-activated dynamic looping for endogenous gene expression control
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Dynamics of the 4D Genome during in Vivo Lineage Specification and Differentiation
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The Intertwined Roles of Transcription and Repair Proteins
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Jpx RNA regulates CTCF anchor site selection and formation of chromosome loops
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Epigenetic Regulation of BDNF Gene during Development and Diseases
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Crossed wires: 3D genome misfolding in human disease
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- Authors
- Phillips-Cremins, J. E., Sauria, M. E. G., Sanyal, A., Gerasimova, T. I., Lajoie, B. R., Bell, J. S. K., Ong, C.-T., Hookway, T. A., Guo, C., Sun, Y., Bland, M. J., Wagstaff, W., Dalton, S., McDevitt, T. C., Sen, R., Dekker, J., Taylor, J., & Corces, V. G.
- Affiliations
- Emory University (US)
- University of Massachusetts Chan Medical School (US)
- National Institute on Aging (US)
- Georgia Institute of Technology (US)
- University of Georgia (US)
- Corresponding author
- Dekker, Job
- Taylor, James
- Corces, Victor G.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 153
- Issue
- 6
- Pages
- 1281-1295
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3712340
- OpenAlex
- W2018658338
- Cited by
- 1,187
- References
- 62
- Citations by year
- 2026: 40 · 2025: 47 · 2024: 60 · 2023: 74 · 2022: 66 · 2021: 87 · 2020: 104 · 2019: 120 · 2018: 117 · 2017: 125 · 2016: 104 · 2015: 98 · 2014: 99 · 2013: 45
- FWCI
- 51.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institutes of Health (1f32ns065603-01)
- National Human Genome Research Institute (RC2HG005542, R01HG003143)
- National Institute of General Medical Sciences (T32GM008490, R01GM035463, P01GM85354, P01GM085354)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK065806)
- National Institute of Neurological Disorders and Stroke (F32 NS065603, 5F32NS065603)
- 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 › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- 3D genome organization, chromatin structure, cell type-specific chromatin, lineage commitment, embryonic stem cells, neural progenitor cells, CTCF, Mediator complex, cohesin, SMC1A, MED12, enhancer-promoter interactions, chromatin looping, cell fate determination
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Animals, Chromatin, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Nuclear Proteins, Promoter Regions, Genetic, Repressor Proteins, Genome, Sequence Analysis, DNA, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Cell Lineage, Mice, Embryonic Stem Cells, Genome-Wide Association Study, Gene Knockdown Techniques, Mediator Complex, Neural Stem Cells
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