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Published on: September 7, 2017
Genome-wide characterization of dynamic DNA 5-hydroxymethylcytosine and TET2-related DNA demethylation during breast
Shuang-Ling Wu1,2, Lin Yang2, Changcai Huang3
1Department of Surgical Oncology and Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110000, China.
Background:
Breast tumorigenesis is a complex and multistep process accompanied by both genetic and epigenetic dysregulation. In contrast to the extensive studies on DNA epigenetic modifications 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in malignant breast tumors, their roles in the early phases of breast tumorigenesis remain ambiguous.
Results:
DNA 5hmC and 5mC exhibited a consistent and significant decrease from usual ductal hyperplasia to atypical ductal hyperplasia and subsequently to ductal carcinoma in situ (DCIS). However, 5hmC showed a modest increase in invasive ductal breast cancer compared to DCIS. Genomic analyses showed that the changes in 5hmC and 5mC levels occurred around the transcription start sites (TSSs), and the modification levels were strongly correlated with gene expression levels. Meanwhile, it was found that differentially hydroxymethylated regions (DhMRs) and differentially methylated regions (DMRs) were overlapped in the early phases and accompanied by the enrichment of active histone marks. In addition, TET2-related DNA demethylation was found to be involved in breast tumorigenesis, and four transcription factor binding sites (TFs: ESR1, FOXA1, GATA3, FOS) were enriched in TET2-related DhMRs/DMRs. Intriguingly, we also identified a certain number of common DhMRs between tumor samples and cell-free DNA (cfDNA).
Conclusions:
Our study reveals that dynamic changes in DNA 5hmC and 5mC play a vital role in propelling breast tumorigenesis. Both TFs and active histone marks are involved in TET2-related DNA demethylation. Concurrent changes in 5hmC signals in primary breast tumors and cfDNA may play a promising role in breast cancer screening.
Insights
Dynamic changes in DNA 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) are crucial in early breast cancer development. These epigenetic marks, along with TET2, transcription factors, and histone marks, drive tumorigenesis and may aid in breast cancer screening using cell-free DNA (cfDNA).
Area of Science:
- Epigenetics
- Cancer Biology
- Genomics
Background:
- Breast tumorigenesis involves complex genetic and epigenetic changes.
- The roles of 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in early breast cancer development are not well understood.
Purpose of the Study:
- To investigate the dynamic changes in DNA 5hmC and 5mC during early breast tumorigenesis.
- To explore the relationship between these epigenetic modifications, gene expression, and breast cancer progression.
- To identify potential biomarkers for breast cancer screening.
Main Methods:
- Analysis of DNA 5hmC and 5mC levels across different stages of breast hyperplasia and carcinoma.
- Genomic analysis to identify differentially modified regions (DhMRs and DMRs) and their association with gene expression.
- Investigation of TET2 involvement, transcription factor enrichment, and histone modifications.
- Comparison of epigenetic marks in tumor samples and cell-free DNA (cfDNA).
Main Results:
- A significant decrease in 5hmC and 5mC was observed from usual ductal hyperplasia to ductal carcinoma in situ (DCIS), with a modest increase in 5hmC in invasive breast cancer.
- Epigenetic changes occurred near transcription start sites (TSSs) and correlated with gene expression.
- Overlapping DhMRs and DMRs in early stages were associated with active histone marks and TET2-related DNA demethylation.
- Enrichment of specific transcription factor binding sites (ESR1, FOXA1, GATA3, FOS) in TET2-related regions.
- Common DhMRs were identified between tumor tissue and cfDNA.
Conclusions:
- Dynamic alterations in DNA 5hmC and 5mC are critical drivers of breast tumorigenesis.
- TET2-mediated DNA demethylation, influenced by transcription factors and histone marks, plays a key role.
- Concurrent 5hmC changes in primary tumors and cfDNA show promise for breast cancer screening.
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