Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition
Open accessAbstract
Chromatin is reprogrammed after fertilization to produce a totipotent zygote with the potential to generate a new organism. The maternal genome inherited from the oocyte and the paternal genome provided by sperm coexist as separate haploid nuclei in the zygote. How these two epigenetically distinct genomes are spatially organized is poorly understood. Existing chromosome conformation capture-based methods are not applicable to oocytes and zygotes owing to a paucity of material. To study three-dimensional chromatin organization in rare cell types, we developed a single-nucleus Hi-C (high-resolution chromosome conformation capture) protocol that provides greater than tenfold more contacts per cell than the previous method. Here we show that chromatin architecture is uniquely reorganized during the oocyte-to-zygote transition in mice and is distinct in paternal and maternal nuclei within single-cell zygotes. Features of genomic organization including compartments, topologically associating domains (TADs) and loops are present in individual oocytes when averaged over the genome, but the presence of each feature at a locus varies between cells. At the sub-megabase level, we observed stochastic clusters of contacts that can occur across TAD boundaries but average into TADs. Notably, we found that TADs and loops, but not compartments, are present in zygotic maternal chromatin, suggesting that these are generated by different mechanisms. Our results demonstrate that the global chromatin organization of zygote nuclei is fundamentally different from that of other interphase cells. An understanding of this zygotic chromatin 'ground state' could potentially provide insights into reprogramming cells to a state of totipotency.
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Single-cell Hi-C studies confirm the presence of TADs in individual cells but demonstrate significant variability in their shape.
“Currently, single-cell Hi-C studies confirm the presence of TADs in individual cells but demonstrate significant variability in their shape (i.e., in the folding of DNA within TADs) [142,143,144,145].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [142]
The paper reports variable contact patterns in individual cells, with clusters frequently violating population TAD boundaries (Abstract). It also finds enrichment of contacts within TADs in individual oocytes, but concludes that TADs are population-average features rather than isolated DNA blocks present in each cell. Thus, it supports variability in folding, but not the unqualified claim that individual-cell TADs are confirmed. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOnly a portion of TAD borders are shared between most individual cells, whereas other borders appear to be variable.
“It was also found that only a portion of TAD borders are shared between most individual cells, whereas other borders appear to be variable [142,143].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [142]
Some types of epigenetic modifications, such as changes in chromosome conformation, are still largely unexplored in MDD.
“Some types of epigenetic modifications, such as changes in chromosome conformation are still largely unexplored in MDD.414,415”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [415]
The paper discusses chromosome organization in oocytes and zygotes (Abstract; page unavailable), but does not address major depressive disorder or whether chromosome-conformation changes are largely unexplored in it. Searches for MDD, depression, and psychiatric disease found no passage speaking to that research-gap claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Self-citation
- Authors
- Flyamer, I. M., Gassler, J., Imakaev, M., Brandão, H. B., Ulianov, S. V., Abdennur, N., Razin, S. V., Mirny, L. A., & Tachibana-Konwalski, K.
- Affiliations
- Institute of Molecular Biotechnology (AT)
- Massachusetts Institute of Technology (US)
- Harvard University (US)
- Russian Academy of Sciences (RU)
- Corresponding author
- Mirny, Leonid A.
- Tachibana-Konwalski, Kikuë
- ORCID
- Venue
- Nature
- Published
- 2017-03-29
- Volume
- 544
- Issue
- 7648
- Pages
- 110-114
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5639698
- OpenAlex
- W2599773520
- Cited by
- 753
- References
- 15
- Citations by year
- 2026: 35 · 2025: 61 · 2024: 70 · 2023: 68 · 2022: 81 · 2021: 114 · 2020: 106 · 2019: 94 · 2018: 75 · 2017: 46 · 2016: 2 · 2013: 1
- FWCI
- 35.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Science Foundation (1504942)
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund (W1238)
- Russian Science Foundation (14–24–00022)
- Lomonosov Moscow State University
- Natural Sciences and Engineering Research Council of Canada
- National Institute of General Medical Sciences (R01GM114190)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK107980)
- Institute of Genetics
- FP7 Ideas: European Research Council (336460)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- chromatin organization, 3D genome organization, topologically associating domains, A/B compartments, chromatin looping, totipotency, mouse embryo development
- MeSH terms
- Paternal Inheritance, Maternal Inheritance, Animals, Cell Nucleus, Chromatin, Female, Haploidy, Interphase, Nucleic Acid Conformation, Oocytes, Stochastic Processes, Zygote, Totipotent Stem Cells, Chromosome Positioning, Mice, Cell Transdifferentiation, Single-Cell Analysis, Cellular Reprogramming
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