Abstract
Long noncoding RNAs (lncRNAs) have emerged as key components in multiple cellular processes, although their physiological and pathological functions are not fully understood. To identify cancer-related lncRNAs, we screened for those that are epigenetically silenced in colorectal cancer (CRC). Through a genome-wide analysis of histone modifications in CRC cells, we found that the transcription start sites (TSSs) of 1,027 lncRNA genes acquired trimethylation of histone H3 lysine 4 (H3K4me3) after DNA demethylation. Integrative analysis of chromatin signatures and the DNA methylome revealed that the promoter CpG islands (CGIs) of 66 lncRNA genes contained cancer-specific methylation. By validating the expression and methylation of lncRNA genes in CRC cells, we ultimately identified 20 lncRNAs, including ZNF582-AS1, as targets of epigenetic silencing in CRC. ZNF582-AS1 is frequently methylated in CRC cell lines (87.5%), primary CRCs (77.2%), colorectal adenomas (44.7%) and advanced adenomas (87.8%), suggesting that this methylation is an early event during colorectal tumorigenesis. Methylation of ZNF582-AS1 is associated with poor survival of CRC patients, and ectopic expression of ZNF582-AS1 suppressed colony formation by CRC cells. Our findings offer insight into the association between epigenetic alterations and lncRNA dysregulation in cancer and suggest that ZNF582-AS1 may be a novel tumor-suppressive lncRNA.
Highlights
It was long believed that RNA functions solely to carry information encoded in genes to proteins; recent work has revealed the biological significance of noncoding RNAs
We show that chromatin signatures before and after the removal of DNA methylation led to the robust identification of Long noncoding RNAs (lncRNAs) genes that are epigenetically regulated in colorectal cancer (CRC)
Genes in CRC, we initially examined the chromatin signatures of lncRNA genes in CRC cells
Summary
It was long believed that RNA functions solely to carry information encoded in genes to proteins; recent work has revealed the biological significance of noncoding RNAs. CCAT2 was identified as a novel lncRNA overexpressed in CRC, in which it promotes metastasis and chromosomal instability[10]. These results suggest that lncRNAs can act as oncogenes or tumor suppressors, the functions of the majority of lncRNAs remain to be determined. In addition to DNA methylation, histone modification is tightly associated with chromatin structure and gene transcription. We aimed to identify cancer-related lncRNAs through integrative genome-wide analysis of histone modification and DNA methylation in CRC cells.
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