Cross-Dataset Genomic Proximity and Functional Association of FOXA1 and TET2 at Hypomethylated Regulatory Regions in Colorectal Cancer.
6 affiliations
- 1Department of Thyroid Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China.
- 2National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen 361102, China.
- 3State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361100, China.
- 4Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
- 5Department of Pediatrics, School of Medicine, Xiamen University, Xiamen 361102, China.
- 6Department of Hematology, School of Medicine, Xiamen University, Xiamen 361102, China.
Abstract
Background/objectives
Aberrant DNA methylation plays a critical role in the development and progression of colorectal cancer (CRC). However, how pioneer transcription factors are associated with DNA demethylases at cis-regulatory elements and influence tumor-associated transcriptional programs remains poorly understood. This study investigated the functional relationship between FOXA1 and TET2, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and its association with epigenetic features and malignant phenotypes in CRC.Methods
Public DNA methylation, ChIP-seq, and transcriptomic datasets were integrated with genome-wide genomic-proximity analyses. The association between FOXA1 and TET2 was evaluated by co-immunoprecipitation. FOXA1 and TET2 were individually or simultaneously depleted in HCT116 and SW480 cells, followed by proliferation and invasion assays. In addition, RNA-seq profiles were generated from control, FOXA1-KD, TET2-KD, and Double-KD HCT116 cells to characterize the resulting transcriptional changes.Results
CRC-associated hypomethylated regions showed preferential enrichment of FOXA1- and TET2-associated ChIP-seq signals. At a 500 bp summit-to-summit threshold, FOXA1-TET2 genomic proximity was 30.7-fold higher than expected under chromosome-wise circular permutation (empirical p = 0.000999). FOXA1/TET2-associated loci also showed lower methylation than FOXA1-only loci in TCGA-COAD tumors (median within-patient Δβ = -0.051; paired Wilcoxon p = 5.86 × 10-50), and FOXA1 and TET2 expression was positively correlated in TCGA-COAD tumors (Spearman's ρ = 0.40 and p = 8.5 × 10-10). Co-immunoprecipitation supported the presence of FOXA1 and TET2 within the same protein complex but did not establish direct physical binding. FOXA1 depletion reduced cell-growth-associated and invasion-associated readouts in both CRC cell lines, whereas TET2 depletion increased growth-associated readouts and showed cell-line-dependent effects on invasion. Combined FOXA1/TET2 depletion produced an intermediate growth phenotype under the conditions examined. RNA-seq revealed broadly concordant transcriptome-wide changes among the knockdown conditions, with pairwise log2 fold-change correlations ranging from r = 0.835 to 0.920, together with shared and comparison-specific transcriptional responses.
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BibTeX
@article{lyu2026crossdataset,
title = {{Cross-Dataset Genomic Proximity and Functional Association of FOXA1 and TET2 at Hypomethylated Regulatory Regions in Colorectal Cancer.}},
author = {Donglu Lyu and Beile Lyu and Qingqing Qin and Chengtian Gao and Jie Hu and Fengyang Cao and Heying Luo and Jun Ren and Qiyuan Li and Ying Zhou and Han Jiang},
journal = {Cancers},
year = {2026},
month = sep,
doi = {10.3390/cancers18193110},
url = {https://europepmc.org/article/MED/42882805},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cross-Dataset Genomic Proximity and Functional Association of FOXA1 and TET2 at Hypomethylated Regulatory Regions in Colorectal Cancer.
AU - Donglu Lyu
AU - Beile Lyu
AU - Qingqing Qin
AU - Chengtian Gao
AU - Jie Hu
AU - Fengyang Cao
AU - Heying Luo
AU - Jun Ren
AU - Qiyuan Li
AU - Ying Zhou
AU - Han Jiang
PY - 2026
DA - 2026/09/25
JO - Cancers
DO - 10.3390/cancers18193110
UR - https://europepmc.org/article/MED/42882805
AB - Background/objectives Aberrant DNA methylation plays a critical role in the development and progression of colorectal cancer (CRC). However, how pioneer transcription factors are associated with DNA demethylases at cis-regulatory elements and influence tumor-associated transcriptional programs remains poorly understood. This study investigated the functional relationship between FOXA1 and TET2, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and its association with epigenetic features and malignant phenotypes in CRC.Methods Public DNA methylation, ChIP-seq, and transcriptomic datasets were integrated with genome-wide genomic-proximity analyses. The association between FOXA1 and TET2 was evaluated by co-immunoprecipitation. FOXA1 and TET2 were individually or simultaneously depleted in HCT116 and SW480 cells, followed by proliferation and invasion assays. In addition, RNA-seq profiles were generated from control, FOXA1-KD, TET2-KD, and Double-KD HCT116 cells to characterize the resulting transcriptional changes.Results CRC-associated hypomethylated regions showed preferential enrichment of FOXA1- and TET2-associated ChIP-seq signals. At a 500 bp summit-to-summit threshold, FOXA1-TET2 genomic proximity was 30.7-fold higher than expected under chromosome-wise circular permutation (empirical p = 0.000999). FOXA1/TET2-associated loci also showed lower methylation than FOXA1-only loci in TCGA-COAD tumors (median within-patient Δβ = -0.051; paired Wilcoxon p = 5.86 × 10-50), and FOXA1 and TET2 expression was positively correlated in TCGA-COAD tumors (Spearman's ρ = 0.40 and p = 8.5 × 10-10). Co-immunoprecipitation supported the presence of FOXA1 and TET2 within the same protein complex but did not establish direct physical binding. FOXA1 depletion reduced cell-growth-associated and invasion-associated readouts in both CRC cell lines, whereas TET2 depletion increased growth-associated readouts and showed cell-line-dependent effects on invasion. Combined FOXA1/TET2 depletion produced an intermediate growth phenotype under the conditions examined. RNA-seq revealed broadly concordant transcriptome-wide changes among the knockdown conditions, with pairwise log2 fold-change correlations ranging from r = 0.835 to 0.920, together with shared and comparison-specific transcriptional responses.
SN - 2072-6694
ER -