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Methylation patterns and chromatin accessibility in neuroendocrine lung cancer

Arbajian, Elsa LU ; Aine, Mattias LU ; Karlsson, Anna LU ; Vallon-Christersson, Johan LU orcid ; Brunnström, Hans LU orcid ; Davidsson, Josef LU ; Mohlin, Sofie LU orcid ; Planck, Maria LU and Staaf, Johan LU orcid (2020) In Cancers 12(8). p.1-17
Abstract

Lung cancer is the worldwide leading cause of death from cancer. Epigenetic modifications such as methylation and changes in chromatin accessibility are major gene regulatory mechanisms involved in tumorigenesis and cellular lineage commitment. We aimed to characterize these processes in the context of neuroendocrine (NE) lung cancer. Illumina 450K DNA methylation data were collected for 1407 lung cancers including 27 NE tumors. NE differentially methylated regions (NE-DMRs) were identified and correlated with gene expression data for 151 lung cancers and 31 human tissue entities from the Genotype-Tissue Expression (GTEx) consortium. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were... (More)

Lung cancer is the worldwide leading cause of death from cancer. Epigenetic modifications such as methylation and changes in chromatin accessibility are major gene regulatory mechanisms involved in tumorigenesis and cellular lineage commitment. We aimed to characterize these processes in the context of neuroendocrine (NE) lung cancer. Illumina 450K DNA methylation data were collected for 1407 lung cancers including 27 NE tumors. NE differentially methylated regions (NE-DMRs) were identified and correlated with gene expression data for 151 lung cancers and 31 human tissue entities from the Genotype-Tissue Expression (GTEx) consortium. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed on eight lung cancer cell lines, including three NE cell lines, to identify neuroendocrine specific gene regulatory elements. We identified DMRs with methylation patterns associated with differential gene expression and an NE tumor phenotype. DMR-associated genes could further be split into six functional modules, including one highly specific gene module for NE lung cancer showing high expression in both normal and malignant brain tissue. The regulatory potential of NE-DMRs was further validated in vitro using paired ATAC-and RNA-seq and revealed both proximal and distal regulatory elements of canonical NE-marker genes such as CHGA, NCAM1, INSM1, as well as a number of novel candidate markers of NE lung cancer. Using multilevel genomic analyses of both tumor bulk tissue and lung cancer cell lines, we identified a large catalogue of gene regulatory elements related to the NE phenotype of lung cancer.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ATAC-seq, DNA methylation, Lung cancer, Neuroendocrine lung cancer, Open chromatin
in
Cancers
volume
12
issue
8
article number
2003
pages
17 pages
publisher
MDPI AG
external identifiers
  • pmid:32707835
  • scopus:85088304217
ISSN
2072-6694
DOI
10.3390/cancers12082003
language
English
LU publication?
yes
id
38bc8b67-3847-4b77-8382-75c31dfbc25b
date added to LUP
2020-09-10 12:53:40
date last changed
2024-03-20 16:19:06
@article{38bc8b67-3847-4b77-8382-75c31dfbc25b,
  abstract     = {{<p>Lung cancer is the worldwide leading cause of death from cancer. Epigenetic modifications such as methylation and changes in chromatin accessibility are major gene regulatory mechanisms involved in tumorigenesis and cellular lineage commitment. We aimed to characterize these processes in the context of neuroendocrine (NE) lung cancer. Illumina 450K DNA methylation data were collected for 1407 lung cancers including 27 NE tumors. NE differentially methylated regions (NE-DMRs) were identified and correlated with gene expression data for 151 lung cancers and 31 human tissue entities from the Genotype-Tissue Expression (GTEx) consortium. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed on eight lung cancer cell lines, including three NE cell lines, to identify neuroendocrine specific gene regulatory elements. We identified DMRs with methylation patterns associated with differential gene expression and an NE tumor phenotype. DMR-associated genes could further be split into six functional modules, including one highly specific gene module for NE lung cancer showing high expression in both normal and malignant brain tissue. The regulatory potential of NE-DMRs was further validated in vitro using paired ATAC-and RNA-seq and revealed both proximal and distal regulatory elements of canonical NE-marker genes such as CHGA, NCAM1, INSM1, as well as a number of novel candidate markers of NE lung cancer. Using multilevel genomic analyses of both tumor bulk tissue and lung cancer cell lines, we identified a large catalogue of gene regulatory elements related to the NE phenotype of lung cancer.</p>}},
  author       = {{Arbajian, Elsa and Aine, Mattias and Karlsson, Anna and Vallon-Christersson, Johan and Brunnström, Hans and Davidsson, Josef and Mohlin, Sofie and Planck, Maria and Staaf, Johan}},
  issn         = {{2072-6694}},
  keywords     = {{ATAC-seq; DNA methylation; Lung cancer; Neuroendocrine lung cancer; Open chromatin}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  pages        = {{1--17}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Methylation patterns and chromatin accessibility in neuroendocrine lung cancer}},
  url          = {{http://dx.doi.org/10.3390/cancers12082003}},
  doi          = {{10.3390/cancers12082003}},
  volume       = {{12}},
  year         = {{2020}},
}