title: 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.
authors: Department of Genetics and Genome Sciences, Department of Biochemistry.
authors: Callie R
authors: CR
authors: Merry
authors: Department of Genetics and Genome Sciences.
authors: Megan E
authors: ME
authors: Forrest
authors: Department of Genetics and Genome Sciences.
authors: Jessica N
authors: JN
authors: Sabers
authors: Case Comprehensive Cancer Center and.
authors: Lydia
authors: L
authors: Beard
authors: Department of Genetics and Genome Sciences.
authors: Xing-Huang
authors: XH
authors: Gao
authors: Department of Genetics and Genome Sciences.
authors: Maria
authors: M
authors: Hatzoglou
authors: Case Comprehensive Cancer Center and Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors: Mark W
authors: MW
authors: Jackson
authors: Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center and.
authors: Zhenghe
authors: Z
authors: Wang
authors: Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center and.
authors: Sanford D
authors: SD
authors: Markowitz
authors: Department of Genetics and Genome Sciences, Department of Biochemistry, Case Comprehensive Cancer Center and dr.ahmad.khalil@gmail.com.
authors: Ahmad M
authors: AM
authors: Khalil
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D045325:HCT116 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000502:physiology; D062085:RNA, Long Noncoding
chemical_list: D002843:Chromatin; D004273:DNA, Neoplasm; D062085:RNA, Long Noncoding; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human