Aberrant transcriptional regulations in cancers: genome, transcriptome and epigenome analysis of lung adenocarcinoma cell lines.
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.
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
Ayako
A
Suzuki
Division of TR, The Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
Hideki
H
Makinoshima
Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
Hiroyuki
H
Wakaguri
Division of TR, The Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
Hiroyasu
H
Esumi
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
Sumio
S
Sugano
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan Division of TR, The Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.
Takashi
T
Kohno
Division of TR, The Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
Katsuya
K
Tsuchihara
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan ysuzuki@hgc.jp.
Yutaka
Y
Suzuki
D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D023281:Genomics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009154:Mutation; D012319:RNA Polymerase II / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D059467:Transcriptome
D006657:Histones; D012319:RNA Polymerase II