Aberrant transcriptional regulations in cancers: genome, transcriptome and epigenome analysis of lung adenocarcinoma cell lines

Abstract

Here we conducted an integrative multi-omics analysis to understand how cancers harbor various types of aberrations at the genomic, epigenomic and transcriptional levels. In order to elucidate biological relevance of the aberrations and their mutual relations, we performed whole-genome sequencing, RNA-Seq, bisulfite sequencing and ChIP-Seq of 26 lung adenocarcinoma cell lines. The collected multi-omics data allowed us to associate an average of 536 coding mutations and 13,573 mutations in promoter or enhancer regions with aberrant transcriptional regulations. We detected the 385 splice site mutations and 552 chromosomal rearrangements, representative cases of which were validated to cause aberrant transcripts. Averages of 61, 217, 3687 and 3112 mutations are located in the regulatory regions which showed differential DNA methylation, H3K4me3, H3K4me1 and H3K27ac marks, respectively. We detected distinct patterns of aberrations in transcriptional regulations depending on genes. We found that the irregular histone marks were characteristic to EGFR and CDKN1A, while a large genomic deletion and hyper-DNA methylation were most frequent for CDKN2A. We also used the multi-omics data to classify the cell lines regarding their hallmarks of carcinogenesis. Our datasets should provide a valuable foundation for biological interpretations of interlaced genomic and epigenomic aberrations.

Regulation of Gene Expression by Sodium Valproate in Epithelial-to-Mesenchymal Transition

“…Future studies should analyze samples after VPA administration by RNA-Seq to reveal its effects on gene expression and regulation. Acetylated histone H3K27 is typically localized in the enhancer and active promoter regions and is known to activate gene expression [20,45]. Our observation that H3K27ac is reduced in whole cells by TGF-b1 stimulation suggests that the TGF-b1-induced down-regulation of gene expression was caused by a decrease of H3K27ac.…”

“…ChIP experiments were performed following a previously described protocol [19] using modified reagents [20]. Cells (1 9 10 7 ) were cross-linked with 1 % formaldehyde for 10 min at room temperature.…”

Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC

“…3A). To investigate the DNA methylation status in NSCLC cell lines in more detail and resolution, we utilized BS-seq and RNA-seq data in 26 LUAD cell lines (30). In all 9 NSCLC cell lines with high MYEOV expression, we observed DNA hypomethylation in the 5 0 UTR region (Fig.…”

“…30) within REP522 elements with or without the CAGE-defined promoters. In PC-14 LUAD cells, enrichment of H3K4me3, H3K27ac, and RNA polymerase II was noted in REP522 elements with promoters, but not in those without promoters, confirming transcriptional activation of promoter regions.…”

“…3B). To consolidate the epigenetic regulation of MYEOV, we compared histone3 modifications in SAECs and A549 LUAD cells (30). In A549 cells, the MYEOV gene locus was enriched with active marks (H3K4me3, H3K9/14ac, and H3K27ac) in contrast with SAECs (Fig.…”