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Updated: Apr 5, 2026
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer
Callie R Merry1, Megan E Forrest2, Jessica N Sabers2
1Department of Genetics and Genome Sciences, Department of Biochemistry.
Abstract:
The cancer epigenome exhibits global loss of DNA methylation, which contributes to genomic instability and aberrant gene expression by mechanisms that are yet to be fully elucidated. We previously discovered over 3300 long non-coding (lnc)RNAs in human cells and demonstrated that specific lncRNAs regulate gene expression via interactions with chromatin-modifying complexes. Here, we tested whether lncRNAs could also associate with DNA methyltransferases to regulate DNA methylation and gene expression. Using RIP-seq, we identified a subset of lncRNAs that interact with the DNA methyltransferase DNMT1 in a colon cancer cell line, HCT116. One lncRNA, TCONS_00023265, which we named DACOR1 (DNMT1-associated Colon Cancer Repressed lncRNA 1), shows high, tissue-specific expression in the normal colon (including colon crypts) but was repressed in a panel of colon tumors and patient-derived colon cancer cell lines. We identified the genomic occupancy sites of DACOR1, which we found to significantly overlap with known differentially methylated regions (DMRs) in colon tumors. Induction of DACOR1 in colon cancer cell lines significantly reduced their ability to form colonies in vitro, suggesting a growth suppressor function. Consistent with the observed phenotype, induction of DACOR1 led to the activation of tumor-suppressor pathways and attenuation of cancer-associated metabolic pathways. Notably, DACOR1 induction resulted in down-regulation of Cystathionine β-synthase, which is known to lead to increased levels of S-adenosyl methionine-the key methyl donor for DNA methylation. Collectively, our results demonstrate that deregulation of DNMT1-associated lncRNAs contributes to aberrant DNA methylation and gene expression during colon tumorigenesis.
Insights
Long non-coding RNAs (lncRNAs) can interact with DNA methyltransferases to regulate DNA methylation and gene expression. A specific lncRNA, DACOR1, acts as a tumor suppressor in colon cancer by reversing aberrant methylation patterns.
Area of Science:
- Epigenetics and Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Cancer epigenomes show global DNA hypomethylation, leading to genomic instability and altered gene expression.
- Long non-coding RNAs (lncRNAs) are known regulators of gene expression through chromatin modification complexes.
- The role of lncRNAs in regulating DNA methylation via DNA methyltransferases remains largely unexplored.
Purpose of the Study:
- To investigate whether lncRNAs can associate with DNA methyltransferases (DNMTs) to control DNA methylation and gene expression.
- To identify specific lncRNAs that interact with DNMT1 in colon cancer cells.
- To characterize the function of a novel DNMT1-interacting lncRNA, DACOR1, in colon tumorigenesis.
Main Methods:
- RNA immunoprecipitation followed by sequencing (RIP-seq) to identify lncRNAs interacting with DNMT1.
- Analysis of DACOR1 expression in normal colon tissues versus colon tumors and cell lines.
- Genomic occupancy mapping of DACOR1 and comparison with differentially methylated regions (DMRs).
- In vitro colony formation assays and pathway analysis upon DACOR1 induction in cancer cell lines.
Main Results:
- A subset of lncRNAs, including DACOR1, were found to interact with DNMT1 in HCT116 colon cancer cells.
- DACOR1 is highly expressed in normal colon tissue but repressed in colon tumors and cancer cell lines.
- DACOR1 genomic occupancy significantly overlaps with tumor-specific DMRs.
- DACOR1 induction suppressed colon cancer cell growth, activated tumor suppressor pathways, and attenuated cancer-associated metabolic pathways.
- DACOR1 induction led to decreased Cystathionine β-synthase expression, reducing S-adenosyl methionine levels.
Conclusions:
- Deregulation of DNMT1-associated lncRNAs, such as DACOR1, contributes to aberrant DNA methylation during colon cancer development.
- DACOR1 functions as a tumor suppressor by reversing epigenetic alterations and inhibiting cancer cell proliferation.
- This study reveals a novel mechanism by which lncRNAs regulate the cancer epigenome and highlights DACOR1 as a potential therapeutic target.
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