Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming
Open accessAbstract
Pluripotent genomes are folded in a topological hierarchy that reorganizes during differentiation. The extent to which chromatin architecture is reconfigured during somatic cell reprogramming is poorly understood. Here we integrate fine-resolution architecture maps with epigenetic marks and gene expression in embryonic stem cells (ESCs), neural progenitor cells (NPCs), and NPC-derived induced pluripotent stem cells (iPSCs). We find that most pluripotency genes reconnect to target enhancers during reprogramming. Unexpectedly, some NPC interactions around pluripotency genes persist in our iPSC clone. Pluripotency genes engaged in both "fully-reprogrammed" and "persistent-NPC" interactions exhibit over/undershooting of target expression levels in iPSCs. Additionally, we identify a subset of "poorly reprogrammed" interactions that do not reconnect in iPSCs and display only partially recovered, ESC-specific CTCF occupancy. 2i/LIF can abrogate persistent-NPC interactions, recover poorly reprogrammed interactions, reinstate CTCF occupancy, and restore expression levels. Our results demonstrate that iPSC genomes can exhibit imperfectly rewired 3D-folding linked to inaccurately reprogrammed gene expression.
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No statistical methods were used to pre-determine sample sizes, but the sample sizes are similar to those reported in previous publications.
“No statistical methods were used to pre-determine sample sizes but our sample sizes are similar to those reported in previous publications17,27,28.”
From Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression (2020) · cites this paper as [28]
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References 48 · Cited by 134
- Authors
- Beagan, J. A., Gilgenast, T. G., Kim, J., Plona, Z., Norton, H. K., Hu, G., Hsu, S. C., Shields, E. J., Lyu, X., Apostolou, E., Hochedlinger, K., Corces, V. G., Dekker, J., & Phillips-Cremins, J. E.
- Affiliations
- University of Pennsylvania (US)
- Emory University (US)
- Massachusetts General Hospital (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 18
- Issue
- 5
- Pages
- 611-624
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4859942
- OpenAlex
- W2345818719
- Cited by
- 134
- References
- 48
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 10 · 2023: 6 · 2022: 9 · 2021: 10 · 2020: 15 · 2019: 21 · 2018: 23 · 2017: 16 · 2016: 10 · 2015: 1
- FWCI
- 12.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Alfred P. Sloan Foundation
- New York Stem Cell Foundation
- National Heart, Lung, and Blood Institute (T32HL007954)
- National Institute of Mental Health (DP2MH110247)
- National Human Genome Research Institute (R01HG003143)
- National Institute of General Medical Sciences (R01GM035463)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK107980)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- 3D genome organization, chromatin structure, somatic cell reprogramming, induced pluripotent stem cells, neural progenitor cells, embryonic stem cells, pluripotency genes, enhancer-promoter interactions, gene expression regulation, chromatin looping
- MeSH terms
- CCCTC-Binding Factor, Animals, Chromatin, Clone Cells, Enhancer Elements, Genetic, Mice, Inbred C57BL, Nucleic Acid Conformation, Protein Binding, Repressor Proteins, Genome, Cell Lineage, Induced Pluripotent Stem Cells, Neural Stem Cells, Cellular Reprogramming
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