Single-cell mapping of DNA G-quadruplex structures in human cancer cells
Open accessAbstract
G-quadruplexes (G4s) are four-stranded DNA secondary structures that form in guanine-rich regions of the genome. G4s have important roles in transcription and replication and have been implicated in genome instability and cancer. Thus far most work has profiled the G4 landscape in an ensemble of cell populations, therefore it is critical to explore the structure–function relationship of G4s in individual cells to enable detailed mechanistic insights into G4 function. With standard ChIP-seq methods it has not been possible to determine if G4 formation at a given genomic locus is variable between individual cells across a population. For the first time, we demonstrate the mapping of a DNA secondary structure at single-cell resolution. We have adapted single-nuclei (sn) CUT&Tag to allow the detection of G4s in single cells of human cancer cell lines. With snG4-CUT&Tag, we can distinguish cellular identity from a mixed cell-type population solely based on G4 features within individual cells. Our methodology now enables genomic investigations on cell-to-cell variation of a DNA secondary structure that were previously not possible.
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G4s were reported to cluster in functional regions and are enriched in genes involved in cancer formation.
“Given that G4s were reported to cluster in functional regions and are enriched in genes involved in cancer formation (59), we hypothesized that cancer-specific genes might contain higher G4-levels, thus explaining the observed exclusive correlation in cancer patients.”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [59]
The Results and discussion section (no page available) reports G4s at gene promoters, supporting their presence in functional regions. It also reports that 28% of the top 50 differentially enriched promoter G4 peaks in MCF7 cells were associated with genes showing increased copy number. It does not establish that G4s are enriched in genes involved in cancer formation. (LLM, conf=0.85)
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“Previously published experimental BG4 peak data indicating G4 formation in two cancerous cell lines (71) was translated from hg38 coordinates to CHM13 coordinates using the LiftOver tool (72).”
InfluentialFeng, Y.-L., He, Z., Luo, Z., Sperti, F., Valverde, I. E., Zhang, W.-L., & Monchaud, D. (2023) · iScience · doi:10.1016/j.isci.2023.106846 · Cited by 17 · see citing works
“13,000, and 15,000 G4 ChIP-seq peaks in leukemia K562, breast cancer MCF7, and osteosarcoma U2OS cells, respectively).(12,15) This represents a minor fraction (2%) of G4FSs detected by G4-seq, likely due to the repressive role of the chromatin packing.”
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“The c-Myc and Esr1 promoters served as positive and negative controls, respectively, based on publicly available BG4 ChIP-seq data from MCF-7 cells [ 46 ].”
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DNA G-quadruplex structures act as functional elements in α- and β-globin enhancers
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InfluentialSelf-citationThe iMab antibody selectively binds to intramolecular and intermolecular i-motif structures
Ruggiero, E., Marušič, M., Zanin, I., Martinez, C. D. P., Christ, D., Plavec, J., & Richter, S. N. (2024) · bioRxiv · doi:10.1093/nar/gkae1305 · Cited by 10 · see citing works
“In unfixed chromatin, the results obtained with iMab were strikingly similar to those obtained with BG4 for G4s (11, 29, 30), with the main difference being the level of expression of the genes presenting folded iMs versus G4s in their promoter.”
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“To measure this, we used the G4-selective antibody BG4 4 and performed CUT&Tag 7 coupled with qPCR to compare the ef fi ciency of BG4 in enriching for MYC-G4, targeted by ATENA, against 3 independent validated G4 sites (MAZ, RPA3, RBBP4) that should not be affected, as they are not targeted by ATENA.”
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Self-citationIn situ tools for chromatin structural epigenomics
Henikoff, S., & Ahmad, K. (2022) · Protein Science · doi:10.1002/pro.4458 · Cited by 10 · see citing works
“For example, multiple groups have adapted CUT&RUN or CUT&Tag for profiling RNADNA hybrids (R-loops) and/or DNA G-quadruplexes,94–96 including in single cells.(96) In addition, a proximity dependent RNA profiling method based on CUT&Tag (RT&Tag) has recently been applied to the genome-wide mapping of chromatin-associat…”
MethodHow DNA secondary structures drive replication fork instability
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“CUT&Tag and its modi fi ed versions typically employ high-salt concentrations (e.g. 150 – 300 mM NaCl or 300 mM KCl) to prevent untargeted tagmentation by protein A-Tn5 10,14,15,17,18 .”
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“Paired with single–nuclei techniques for non-B DNA motif detection, they can reveal cell-to-cell heterogeneity [ 390 ].”
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“First, we identified G4 consensus sites across six different cell lines (NHEK, HaCaT, U2OS, K562, HeLa, and K562) using ChIP-seq and CUT&Tag data generated with the structure-specific antibody, BG4 (6, 8, 13, 20, 65, 66).”
Rapid degradation of DHX36 revealing its transcriptional role by interacting with G‐quadruplex
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G-quadruplex landscape and its regulation revealed by a new antibody capture method
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“Native G4 landscape has been described using CUT&Tag approaches with significant applications for single-cell mapping of G4s [40–43].”
Wang, Z., He, X., Zhang, X., Spiegel, J., Flynn, S. M., & Balasubramanian, S. (2026) · Nature Chemistry · doi:10.1038/s41557-026-02111-y · Cited by 4 · see citing works
“The number of peaks used (SMARCA4 peaks n = 15380, FUS peaks n = 14269, BG4 peaks n = 18729).”
InfluentialSelf-citationssG4-seq for global profiling of strand-specific G-quadruplex structures in mammalian genomes
Li, S., Wang, R., Zhang, J., Cao, C., Bai, J., Cai, Z., Ye, R., Chen, J., Liu, W., Chen, L., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-66895-2 · Cited by 5 · see citing works
“1i) further show that, compared with other G4 detection methods, ssG4-seq provides a higher signal-to-noise ratio than G4 CUT&Tag-Li and BG4 ChIP-seq, and iscomparable to Chem-map, G4 CUT&Tag-Hui, andG4access.”
InfluentialHile, S. E., Weissensteiner, M. H., Pytko, K. G., Dahl, J. M., Kejnovský, E., Kejnovská, I., Hedglin, M., Georgakopoulos‐Soares, I., Makova, K. D., & Eckert, K. A. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf352 · Cited by 3 · see citing works
“Although there are up to 700 000 putative G4 sequences in the human genome [ 21 ], only 10 000 may form G4 structures in a population of cells [ 13 ], and as few as 700 may form G4 structures at any given time in a single cell [ 22 ].”
Sequencing DNA methylation and hydroxymethylation at co-occurring chromatin features
Tavares, R. D. C. A., Dhir, S., He, X., Monahan, J. M., Taipale, M., Golder, P. Y., Ciau-Uitz, A., Gosal, W. S., Tannahill, D., & Balasubramanian, S. (2026) · Nature Communications · doi:10.1038/s41467-026-69429-6 · Cited by 3 · see citing works
Self-citationStability of non-canonical nucleic acid structure as a potential modulator of cell fate
Takahashi, S., Tateishi-Karimata, H., & Sugimoto, N. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkaf1486 · Cited by 3 · see citing works
“G4 detection using cleavage under targets and tagmentation (CUT&Tag) techniques has also been used [ 311 , 312 ]. iM detection was also developed using an iM-targeting antibody [ 313 ].”
Li, J., Li, L., Tan, Y., Yin, M.-D., Li, Y., Yin, D., An, J., Zhuang, G.-L., Qian, M.-X., & Hu, J.-C. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1330 · Cited by 3 · see citing works
“The G-quadruplex (G4) CUT&Tag BED file for U2OS cells was downloaded from GEO (accession number GSE181373) [ 57 ].”
Non-canonical DNA in human and other ape telomere-to-telomere genomes
Smeds, L., Kamali, K., Kejnovská, I., Kejnovský, E., Chiaromonte, F., & Makova, K. D. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf298 · Cited by 28 · see citing works
“…each region from CHM13 to hg38 and summed up all unique regions on anchored chromosomes (meaning if multiple repeat copies in CHM13 mapped to a single region in hg38, this was only counted once, and we did not consider hits on un-placed (“Un”) or random scaffolds as these were not used in [ 71 ]).”
InfluentialShining a light on cell biology of the nucleus with single-cell sequencing
van den Berg, J., & Zeller, P. J. (2025) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2025.102468 · Cited by 3 · see citing works
Data augmentation with generative models improves detection of Non-B DNA structures
Cherednichenko, O., & Poptsova, M. (2024) · Comput. Biol. Medicine · doi:10.1016/j.compbiomed.2024.109440 · Cited by 3 · see citing works
Untargeted CUT&Tag and BG4 CUT&Tag are both enriched at G-quadruplexes and accessible chromatin
Thompson, M. D., & Byrd, A. K. (2024) · bioRxiv · doi:10.1101/2024.09.26.615263 · Cited by 3
Analysis of live cell data with G-DNABERT supports a role for G-quadruplexes in chromatin loopingPreprint
Konovalov, D., Umerenkov, D., Herbert, A. G., & Poptsova, M. S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.21.599985 · Cited by 2 · see citing works
“G4 CUT&Tag method detects around 18 000 G4s 13 .”
HLTF Prevents G4 Accumulation and Promotes G4-induced Fork Slowing to Maintain Genome Stability
Bai, G., Endres, T., Kühbacher, U., Greer, B. H., Peacock, E. M., Crossley, M. P., Sathirachinda, A., Cortez, D., Eichman, B., & Cimprich, K. A. (2023) · bioRxiv · doi:10.1101/2023.10.27.563641 · Cited by 3
Roy, L., Roy, A., Bose, D., Banerjee, N., & Chatterjee, S. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2268200 · Cited by 3 · see citing works
Konovalov, D., Umerenkov, D., Herbert, A. G., & Poptsova, M. S. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1007 · Cited by 4 · see citing works
“In a side-by-side comparison, the signal-to-noise ratio was higher with this method compared to ChIP-seq approaches based on BG4 and an artificially constructed GQ-binding protein [ 11 ].”
Shu, H., Xiao, K., Zhu, W., Zhang, R., Tao, T., & Sun, X. S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146874 · Cited by 2 · see citing works
“We collected the in vivo G4 data from the public high-throughput experiments in breast cancer including 22 breast cancer patient-derived tumor xenograft (PDTX) models (27 biological samples) and the MCF7 breast adenocarcinoma cell line [29,31].”
Knot-knot chronicles: unveiling the G-quadruplexes
Sharma, H., & Garg, R. (2025) · Critical Reviews in Biotechnology · doi:10.1080/07388551.2024.2435960 · Cited by 2 · see citing works
G-quadruplex and 8-oxo-7,8-dihydroguanine across the genome: methodologies and crosstalk
An, J., Yin, M., & Hu, J. (2022) · Genome Instability & Disease · doi:10.1007/s42764-022-00082-1 · Cited by 2 · see citing works
“Recently, the CUT&TAG technique was adopted to replace traditional ChIP-seq and enabled G4 detection in fewer cells with higher sensitivity (Hui et al., 2022; Li et al., 2021; Lyu et al., 2022).”
MethodiDualG4: A Dual-Channel Deep Learning Framework for Predicting In Vivo G-Quadruplexes
Li, H., Dong, L., Jia, Y., Zheng, C.-H., & Wei, P. (2026) · Biomolecules · doi:10.3390/biom16050693 · Cited by 1
“We utilized processed peak data provided by the original authors for three distinct cell lines: K562 (human chronic myelogenous leukemia) G4 ChIP-seq data (GSE107690) [19]; HepG2 (human liver cancer) G4 ChIP-seq data (GSE145090) [20]; and MCF7 (human breast cancer) G4 CUT&Tag data (GSE181373) [21].”
Targeting DHODH promoter G-quadruplex to induce ferroptosis in melanoma cells.
Zhang, W., Xu, Q., & Sui, Y. (2025) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2025.153117 · Cited by 1
Dexheimer, T. S., Coussens, N. P., Silvers, T. E., Juneja, P., Jones, E., Gore, S. D., Kunkel, M. W., Doroshow, J. H., & Teicher, B. A. (2025) · SLAS DISCOVERY · doi:10.1016/j.slasd.2025.100284 · Cited by 1 · see citing works
Monti, L., Firth, G., Faria, J. R. C., Kelly, J. M., Flint, G., Galli, S., Maher, T. E., Aye, H. M., & di Antonio, M. (2025) · bioRxiv · doi:10.1093/nar/gkag637 · Cited by 1 · see citing works
“Recombinant BG4 was expressed as previously described [ 58 ].”
Specification of Origins of DNA Replication Within Distinct Chromatin States in Human Cells
Ouyang, M., & Stillman, B. (2026) · bioRxiv · doi:10.64898/2026.10.22.761122
Non-B DNA at the Interface of Metabolism, Genome Stability, and Inflammation
Megalovasilis, G., Bochalis, E., Chartoumpekis, D., Vasquez, K. M., & Georgakopoulos-Soares, I. (2026) · Genes · doi:10.3390/genes17101301
“In addition, most mapping approaches average signals across cell populations, obscuring the transient and heterogeneous formation of these structures at individual loci [178].”
Bartosik, A. R., Bujnowska, M., Stovall, D. B., Ratan, A., & Wang, Y. (2026) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2026.2710103
“…different cell lines (NHEK, HaCaT, U2OS, K562, HeLa and NSC) using ChIP-seq and CUT&Tag data generated with the structure-specific antibody, BG4 (Hänsel-Hertsch et al. 2016; Hänsel-Hertsch et al. 2018; Mao et al. 2018; Hui et al. 2021; C. Li et al. 2021; Zyner et al. 2022; Bartosik et al. 2025).”
G-quadruplex homeostasis is a determinant of PARP inhibitor toxicity in BRCA2-deficient cells
Sharma, A. B., Krwawicz, J., Tappenden, L., Ramlee, M. K., Abugable, A. A., Zhen, X., Khurana, S., Stracker, T. H., & Lakin, N. (2026) · Nature Communications · doi:10.1038/s41467-026-75083-9
“In support of this, although nearly 500,000 potential G4-forming sequences are predicted in the human genome, only a subset form at any given time, and distinct G4 populations are evident across different cell types 14,66 .”
Enzyme tethering for in situ epigenomics
Ahmad, K., Brahma, S., Janssens, D. H., Kind, J., Khyzha, N., Meers, M. P., Ramachandran, S., Zheng, Y., & Henikoff, S. (2026) · Nature Reviews Methods Primers · doi:10.1038/s43586-026-00491-6 · Cited by 1 · see citing works
Karbassi, S., Nikolova, T., Pfeiffer, D., Nakkeeran, S., Anand, R., Frappart, P., Kuhlen, M., & Hofmann, T. G. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.24.714005
“Although the human genome harbors more than 700,000 potential G4-forming sequences 18 , only a minor fraction of them form G4 secondary structures in a natural chromatin context in the cell 19 , and moreover, different cell types form specific G4 subsets 20, 21 .”
G-quadruplexes regulate chromatin accessibility and gene expression in Bloom SyndromePreprint
Su, D., Altmannová, V., Soltys, V., Peters, M. A., Cunniff, C. M., Weir, J. R., & Chan, Y. F. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.03.709275
“To fully establish the causal role of G4s, further studies and more sensitive assays for mapping G4s, such as CUT&Tag or even single-cell assays are required 72,73 .”
Byrd, A. K., & Thompson, M. D. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1338
“( B ) Replicate-averaged untargeted CUT&Tag data as in panel (A) ( n = 3) and BG4 CUT&Tag data ( n = 3) from K562 cells [ 1 ], Biotin ( n = 2), PhenDC3 ( n = 2), and pyridostatin (PDS) ( n = 2) Chem-map data from K562 cells [ 3 ], and A T AC-seq data ( n = 3) from K562 cells [ 15 ] are plotted at a…”
InfluentialVincristine Beyond Mitosis: Uncovering a First Link to G-Quadruplex DNA in Cancer Cells
Porzio, A. D., Persico, C., Romano, F., Barra, A., Aiello, I., D'Auria, L., Abate, S., D'Aria, F., Giancola, C., Cinquegrana, E., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199606
“…cell lines, including HeLa (cervical adenocarcinoma) and U2OS (osteosarcoma) cells—which have been mapped in detail for G4 distribution and dynamics [19]—as well as the highly aggressive and metastatic MDA-MB-231 human breast cancer cell line, largely employed for testing promising G4 binders [20].”
G-quadruplex profiling in complex tissues using single-cell CUT&TagPreprint
Lyu, J., Hetey, S., Castelo‐Branco, G., Bartošovič, M., & Elsässer, S. J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.03.647101 · Cited by 2 · see citing works
“…13.5%, and 16.3% for the mESC-MEF, sorted, and unsorted mouse datasets, respectively, was comparable to a previous G4 scCUT&Tag study on a mixture of two human cell lines, which reported 1,226 fragments with a FRiP score of 26% for U2OS and 819 fragments with a FRiP score of 10.5% for MCF7 (28).”
Influential
- Authors
- Hui, W. W. I., Simeone, A., Zyner, K. G., Tannahill, D., & Balasubramanian, S.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Balasubramanian, Shankar
- Venue
- Scientific Reports
- Published
- 2021-12-08
- Volume
- 11
- Issue
- 1
- Pages
- 23641-23641
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC8654944
- OpenAlex
- W4200323346
- Cited by
- 85
- References
- 29
- Citations by year
- 2026: 10 · 2025: 26 · 2024: 22 · 2023: 18 · 2022: 9
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-01-12)
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Apollo
- Funders
- Cancer Research UK (C9545/A19836)
- Wellcome Trust (209441/Z/17/Z)
- Herchel Smith Funds
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- 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
- G-quadruplex, cell-to-cell variability, human cancer cell lines, genomic instability, cell type annotation, single-nucleus sequencing
- MeSH terms
- DNA, Humans, Neoplasms, Nucleic Acid Conformation, Cell Line, Tumor, G-Quadruplexes, Single-Cell Analysis
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