Methylation patterns and chromatin accessibility in neuroendocrine lung cancer
(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
- Arbajian, Elsa LU ; Aine, Mattias LU ; Karlsson, Anna LU ; Vallon-Christersson, Johan LU ; Brunnström, Hans LU ; Davidsson, Josef LU ; Mohlin, Sofie LU ; Planck, Maria LU and Staaf, Johan LU
- organization
-
- Breast/lungcancer
- LUCC: Lund University Cancer Centre
- The genetics of soft tissue tumors (research group)
- Division of Clinical Genetics
- Division of Molecular Hematology (DMH)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Research Group Lung Cancer (research group)
- Breastcancer-genetics
- Childhood Cancer Research Unit (research group)
- Paediatrics (Lund)
- Division of Translational Cancer Research
- publishing date
- 2020-08-01
- 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
-
- scopus:85088304217
- pmid:32707835
- 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
- 2024-09-19 06:21:04
@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}}, }