Global DNA methylation profiling reveals new insights into epigenetically deregulated protein coding and long noncoding RNAs in CLL. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Subhash, Santhilal; Andersson, Per-Ola; Kosalai, Subazini; Kanduri, Chandrasekhar; Kanduri, Meena
• Is Part Of: Clinical epigenetics. Volume 8:Issue 1(2016)
• Page Start: 1
• Page End: 15
• Publication Date: 2016-12
• Subjects: DNA methylation -- Chronic lymphocytic leukemia -- Hyper/hypomethylated regions -- Repetitive elements and noncoding RNAs; Epigenesis -- Periodicals; Genetic regulation -- Periodicals; Human cytogenetics -- Periodicals; Human molecular genetics -- Periodicals; Cancer -- Genetic aspects -- Periodicals; 611.01816
• DOI: 10.1186/s13148-016-0274-6
• Languages: English
• ISSNs: 1868-7075

Abstract

Abstract Background Methyl-CpG-binding domain protein enriched genome-wide sequencing (MBD-Seq) is a robust and powerful method for analyzing methylated CpG-rich regions with complete genome-wide coverage. In chronic lymphocytic leukemia (CLL), the role of CpG methylated regions associated with transcribed long noncoding RNAs (lncRNA) and repetitive genomic elements are poorly understood. Based on MBD-Seq, we characterized the global methylation profile of high CpG-rich regions in different CLL prognostic subgroups based on IGHV mutational status. Results Our study identified 5800 hypermethylated and 12, 570 hypomethylated CLL-specific differentially methylated genes (cllDMGs) compared to normal controls. From cllDMGs, 40 % of hypermethylated and 60 % of hypomethylated genes were mapped to noncoding RNAs. In addition, we found that the major repetitive elements such as short interspersed elements (SINE) and long interspersed elements (LINE) have a high percentage of cllDMRs (differentially methylated regions) in IGHV subgroups compared to normal controls. Finally, two novel lncRNAs (hypermethylatedCRNDE and hypomethylatedAC012065.7 ) were validated in an independent CLL sample cohort (48 samples) compared with 6 normal sorted B cell samples using quantitative pyrosequencing analysis. The methylation levels showed an inverse correlation to gene expression levels analyzed by real-time quantitative PCR. Notably, survival analysis revealed that hypermethylation ofCRNDE and hypomethylation ofAC012065.7 correlated with an inferior outcome. Conclusions Thus, our comprehensive methylation analysis by MBD-Seq provided novel hyper and hypomethylated long noncoding RNAs, repetitive elements, along with protein coding genes as potential epigenetic-based CLL-signature genes involved in disease pathogenesis and prognosis.