DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer

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.

Long non‐coding RNA metastasis‐associated lung adenocarcinoma transcript 1 promotes lung adenocarcinoma by directly interacting with specificity protein 1

“…One important way that lncRNAs function is to interact with certain critical proteins. Previous studies have confirmed that lncRNAs can directly interact with proteins and regulate gene transcription, 22,23 which implies that malat1 might affect SP1 transcriptional activity Figure 5C). RNA immunoprecipitation experiment using SP1 antibody followed by quantitative real-time PCR for malat1 in A549 cells was also carried out, and the results showed that antibody against SP1 could result in higher enrichment of malat1 RNA compared with the IgG control ( Figure 5D).…”

“…One important way that lncRNAs function is to interact with certain critical proteins. Previous studies have confirmed that lncRNAs can directly interact with proteins and regulate gene transcription, which implies that malat1 might affect SP1 transcriptional activity and target gene expression by interacting with SP1 protein. SP1 belongs to the Sp/KLF family of transcription factors.…”

Relationship Between Noncoding RNA Dysregulation and Epigenetic Mechanisms in Cancer

“…Merry et al have screened for lncRNAs that directly interact with DNMT1 and identifi ed DNMT1-associated colon cancer repressed lncRNA (DACOR1), which is expressed in normal colon and repressed in colon cancer [ 181 ]. Induction of DACOR1 in colon cancer cells suppresses colony formation and downregulates cystathionine β-synthase, which leads to increased levels of S-adenosyl methionine, a key methyl donor for DNA methylation.…”

“…Induction of DACOR1 in colon cancer cells suppresses colony formation and downregulates cystathionine β-synthase, which leads to increased levels of S-adenosyl methionine, a key methyl donor for DNA methylation. Repression of DACOR1 may thus promote colon tumorigenesis by inducing global DNA hypomethylation [ 181 ].…”

The interaction between DNA methylation and long non‐coding RNA during the onset of puberty in goats

“…Here, silencing of MEG3 was shown to reduce miR‐29a expression, which modulates DNMT1 and DNMT3B (Braconi et al, ). In addition, another study revealed that lncRNAs could directly interact with DNMT1 (Merry et al, ). These studies indicate that methylation is a potential factor in regulating lncRNA expression.…”