Journal of Shanghai Jiao Tong University (Medical Science) >

2025 , Vol. 45 >Issue 10: 1261 - 1270

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.10.001

Innovative research team achievement column

Analysis of epigenetic characteristics in colonic tumors of Apcmin/+via spatial ATAC-seq technology

  • LIANG Lebin ,
  • CHEN Huifang ,
  • LAI Shujing ,
  • GU liang ,
  • SU Bing
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  • Department of Microbiology and Immunology, Shanghai Jiao Tong University College of Basic Medical Sciences; Shanghai Institute of Immunology, Shanghai 200025, China
SU Bing, E-mail: bingsu@sjtu.edu.cn.

Received date: 2025-03-15

  Accepted date: 2025-04-03

  Online published: 2025-10-28

Supported by

National Natural Science Foundation of China(32100730);Foundation of State Key Laboratory of Systematic Oncology Medicine(KF2406-93)

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Abstract

Objective ·To investigate the spatial epigenetic characteristics of spontaneous colon tumors in Apcmin/+ mice. Methods ·A spatial assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) technology platform was established using an eight-month-old male Apcmin/+ mouse model with spontaneous colon tumors. One tumor from a mouse was harvested and embedded in OCT compound for serial cryosectioning; one tissue section was stained with hematoxylin-eosin (H-E) to observe its histological characteristics, while an adjacent section was processed using spatial ATAC-seq technology to generate spatially resolved DNA libraries, followed by sequencing to obtain spatial chromatin accessibility data. Another tumor from the same mouse was digested into a single-cell suspension, in which viable single cells were sorted by flow cytometry and processed for single-cell RNA sequencing. The results were integrated with spatial chromatin accessibility data to jointly analyze the epigenetic characteristics of the colon tumor microenvironment. Results ·A stable spatial ATAC-seq platform was successfully established, dividing the tumor into malignant, non-malignant, and malignant-non-malignant boundary regions. Transcription factors enriched in malignant regions included NK2 homeobox 5 (NKX2-5) and transcription factor 3 (TCF3). Analysis of transcription factor enrichment in the 3 regions revealed two distinct expression trends: one showing a gradual decrease from malignant to boundary to non-malignant regions, and the other exhibiting high expression in malignant and boundary regions but low expression in non-malignant regions. Gene analysis across regions revealed significant upregulation of hypoxia response, transforming growth factor (TGF), and Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling pathways in malignant regions, with cell cycle-related functions markedly enhanced. Analysis of cell-cell interactions in the tumor microenvironment revealed significant differences in interaction strength: strong interactions within non-malignant regions, moderate interactions between boundary and non-malignant regions, and weak interactions between malignant and boundary regions as well as between malignant and non-malignant regions. Conclusion ·Colon tumors in Apcmin/+ mice exhibit high spatial heterogeneity; malignant regions were enriched with transcription factors including TCF3, and cell interactions between malignant regions and boundary/non-malignant regions were relatively weak.

Key words： colorectal cancer (CRC); spatial ATAC-seq; epigenetics; single-cell RNA-seq

Cite this article

LIANG Lebin , CHEN Huifang , LAI Shujing , GU liang , SU Bing . Analysis of epigenetic characteristics in colonic tumors of Apcmin/+via spatial ATAC-seq technology[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025 , 45(10) : 1261 -1270 . DOI: 10.3969/j.issn.1674-8115.2025.10.001

References

[1] LEE J, KIM I H, KIM J S, et al. Different clinical characteristics in sporadic young-age onset colorectal cancer[J]. Medicine (Baltimore), 2016, 95(37): e4840.
[2] JASPERSON K W, TUOHY T M, NEKLASON D W, et al. Hereditary and familial colon cancer[J]. Gastroenterology, 2010, 138(6): 2044-2058.
[3] KAKIUCHI H, WATANABE M, USHIJIMA T, et al. Specific 5'- GGGA-3'→5'-GGA-3' mutation of the Apc gene in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine[J]. Proc Natl Acad Sci USA, 1995, 92(3): 910-914.
[4] DOW L E, O'ROURKE K P, SIMON J, et al. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer[J]. Cell, 2015, 161(7): 1539-1552.
[5] ZHAO H, MING T Q, TANG S, et al. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target[J]. Mol Cancer, 2022, 21(1): 144.
[6] LIU T, ZHANG X, DU L T, et al. Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer[J]. Mol Cancer, 2019, 18(1): 43.
[7] STASTNA M, JANECKOVA L, HRCKULAK D, et al. Human colorectal cancer from the perspective of mouse models[J]. Genes (Basel), 2019, 10(10): 788.
[8] ROSENBERG D W, GIARDINA C, TANAKA T. Mouse models for the study of colon carcinogenesis[J]. Carcinogenesis, 2009, 30(2): 183-196.
[9] ST?HL P L, SALMéN F, VICKOVIC S, et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics[J]. Science, 2016, 353(6294): 78-82.
[10] RODRIQUES S G, STICKELS R R, GOEVA A, et al. Slide-seq: a scalable technology for measuring genome-wide expression at high spatial resolution[J]. Science, 2019, 363(6434): 1463-1467.
[11] ZHAI J N, CHEN H R, WONG C C, et al. ALKBH5 drives immune suppression via targeting AXIN2 to promote colorectal cancer and is a target for boosting immunotherapy[J]. Gastroenterology, 2023, 165(2): 445-462.
[12] WEI C, YANG C G, WANG S Y, et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis[J]. Mol Cancer, 2019, 18(1): 64.
[13] DENG Y X, BARTOSOVIC M, MA S, et al. Spatial profiling of chromatin accessibility in mouse and human tissues[J]. Nature, 2022, 609(7926): 375-383.
[14] DENG Y X, BARTOSOVIC M, KUKANJA P, et al. Spatial-CUT&Tag: spatially resolved chromatin modification profiling at the cellular level[J]. Science, 2022, 375(6581): 681-686.
[15] BAYSOY A, BAI Z L, SATIJA R, et al. The technological landscape and applications of single-cell multi-omics[J]. Nat Rev Mol Cell Biol, 2023, 24(10): 695-713.
[16] AMODIO V, LAMBA S, CHILà R, et al. Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance[J]. Cancer Cell, 2023, 41(1): 196-209.e5.
[17] LEVENTAL K R, YU H M, KASS L, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling[J]. Cell, 2009, 139(5): 891-906.
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