Analysis of gene-targeted DNA methylation patterns through the annual cycle in clonal epitypes of Norway spruce
Ontology highlight
ABSTRACT:
ORGANISM(S): Picea abies
PROVIDER: GSE222491 | GEO | 2023/08/01
REPOSITORIES: GEO
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Project description:Acute myeloid leukemia (AML) is a molecularly complex disease characterized by heterogeneous tumor genetic profiles and involving numerous pathogenic mechanisms and pathways. Integration of molecular data types across multiple patient cohorts may advance current genetic approaches for improved sub-classification and understanding of the biology of the disease. Here we analyzed genome-wide DNA methylation in 649 AML patients using Illumina arrays and identified a configuration of 13 subtypes (termed ‘epitypes’) using unbiased clustering. Integration of genetic data revealed that most epitypes were associated with a certain recurrent mutation (or combination) in a majority of patients, yet other epitypes were largely independent. Epitypes demonstrated developmental blockage at discrete stages of myeloid differentiation, revealing epitypes that retain arrested hematopoietic stem cell-like phenotypes. Detailed analyses of DNA methylation patterns identified unique patterns of aberrant hyper- and hypomethylation among epitypes, with variable involvement of transcription factors influencing promoter, enhancer and repressed regions. Patients in epitypes with stem cell-like methylation features showed inferior overall survival along with upregulated stem cell gene expression signatures. We further identified a DNA methylation signature involving STAT motifs associated with FLT3-ITD mutations. Finally, DNA methylation signatures were remarkably stable at relapse for the large majority of patients, and rare epitype switching accompanied loss of the dominant epitype mutations and reversion to stem cell-like methylation patterns. These results demonstrate that DNA methylation-based classification integrates important molecular features of AML to reveal the diverse pathogenic and biological aspects of the disease.
2021-03-09 | GSE159907 | GEO
Project description:Aberrant DNA methylation is frequently observed in breast cancer. However, the relationship between methylation patterns and the heterogeneity of breast cancer has not been comprehensively characterized. Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 188 human breast tumors. Unsupervised bootstrap consensus clustering was performed to identify DNA methylation epigenetic subgroups (epitypes). The Cancer Genome Atlas data, incluing methylation profiles of 669 human breast tumors, was utilized for validation. The identified epitypes were characterized by integration with publicly available genome-wide data, including gene expression levels, DNA copy numbers, whole-exome sequencing data, and chromatin states. We identified seven breast cancer epitypes. One epitype was distinctly associated with basal-like tumors and with BRCA1 mutations, one epitype contained a subset of ERBB2-amplified tumors characterized by multiple additional amplifications and the most complex genomes, and one epitype displayed a methylation profile similar to normal epithelial cells. Luminal tumors were stratified into the remaining four epitypes, with differences in promoter hypermethylation, global hypomethylation, proliferative rates and genomic instability. We observed two dominant patterns of aberrant methylation in breast cancer. One pattern, constitutively methylated in both basal-like and luminal breast cancer, was linked to genes with promoters in a Polycomb-repressed state in normal epithelial cells and displayed no correlation to gene expression levels. The second pattern correlated with gene expression levels and was associated with methylation in luminal tumors and genes with active promoters in normal epithelial cells. Our results suggest that hypermethylation patterns in basal-like breast cancer may have limited influence on tumor progression and instead reflects the repressed chromatin state of the tissue of origin. On the contrary, hypermethylation patterns specific to luminal breast cancer influence gene expression, may contribute to tumor progression, and may present an actionable epigenetic alteration in some luminal breast cancers. Genome-wide DNA methylation analysis of 188 breast cancers using Illumina Human Methylation 450K Beadchips.
2016-02-29 | E-GEOD-75067 | biostudies-arrayexpress
Project description:Aberrant DNA methylation is frequently observed in breast cancer. However, the relationship between methylation patterns and the heterogeneity of breast cancer has not been comprehensively characterized. Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 188 human breast tumors. Unsupervised bootstrap consensus clustering was performed to identify DNA methylation epigenetic subgroups (epitypes). The Cancer Genome Atlas data, incluing methylation profiles of 669 human breast tumors, was utilized for validation. The identified epitypes were characterized by integration with publicly available genome-wide data, including gene expression levels, DNA copy numbers, whole-exome sequencing data, and chromatin states. We identified seven breast cancer epitypes. One epitype was distinctly associated with basal-like tumors and with BRCA1 mutations, one epitype contained a subset of ERBB2-amplified tumors characterized by multiple additional amplifications and the most complex genomes, and one epitype displayed a methylation profile similar to normal epithelial cells. Luminal tumors were stratified into the remaining four epitypes, with differences in promoter hypermethylation, global hypomethylation, proliferative rates and genomic instability. We observed two dominant patterns of aberrant methylation in breast cancer. One pattern, constitutively methylated in both basal-like and luminal breast cancer, was linked to genes with promoters in a Polycomb-repressed state in normal epithelial cells and displayed no correlation to gene expression levels. The second pattern correlated with gene expression levels and was associated with methylation in luminal tumors and genes with active promoters in normal epithelial cells. Our results suggest that hypermethylation patterns in basal-like breast cancer may have limited influence on tumor progression and instead reflects the repressed chromatin state of the tissue of origin. On the contrary, hypermethylation patterns specific to luminal breast cancer influence gene expression, may contribute to tumor progression, and may present an actionable epigenetic alteration in some luminal breast cancers.
2016-02-29 | GSE75067 | GEO
Project description:Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer is not well studied. We performed whole-genome methylation analysis using 450K Illumina BeadArrays on 124 tumors including 83 adenocarcinomas, 23 squamous cell carcinomas, one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), three small cell carcinomas (SCLC) and 12 normal lung tissues. Unsupervised class discovery was performed to identify DNA methylation subgroups with clinicopathological and molecular features. Subgroups were validated in two independent NSCLC cohorts. Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, in both discovery and validation cohorts, remaining four epitypes were associated with differences in clinicopathological and molecular features, including global hypomethylation, promoter hypermethylation, copy number alterations, expression of proliferation-associated genes, association with unsupervised and supervised gene expression phenotypes, KRAS, TP53, KEAP1, SMARCA4, and STK11 mutations, smoking history, and patient outcome. Based on a multicohort approach we conducted a comprehensive survey of genome-wide DNA methylation in lung cancer, identifying a distinct neuroendocrine epitype and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, and patient outcome. Our results bring further understanding of the epigenetic characteristics and molecular diversity in lung cancer generally and in adenocarcinoma specifically. Genome-wide DNA methylation analysis of 124 lung carcinomas and 12 normal lung tissues using Illumina Human Methylation 450K v1.0 Beadchips.
2014-10-05 | E-GEOD-56044 | biostudies-arrayexpress
Project description:Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer is not well studied. We performed whole-genome methylation analysis using 450K Illumina BeadArrays on 124 tumors including 83 adenocarcinomas, 23 squamous cell carcinomas, one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), three small cell carcinomas (SCLC) and 12 normal lung tissues. Unsupervised class discovery was performed to identify DNA methylation subgroups with clinicopathological and molecular features. Subgroups were validated in two independent NSCLC cohorts. Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, in both discovery and validation cohorts, remaining four epitypes were associated with differences in clinicopathological and molecular features, including global hypomethylation, promoter hypermethylation, copy number alterations, expression of proliferation-associated genes, association with unsupervised and supervised gene expression phenotypes, KRAS, TP53, KEAP1, SMARCA4, and STK11 mutations, smoking history, and patient outcome. Based on a multicohort approach we conducted a comprehensive survey of genome-wide DNA methylation in lung cancer, identifying a distinct neuroendocrine epitype and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, and patient outcome. Our results bring further understanding of the epigenetic characteristics and molecular diversity in lung cancer generally and in adenocarcinoma specifically.
2014-10-05 | GSE56044 | GEO
Project description:We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes and tumor suppressor genes. In contrast, we also identified genes with copy number gains, high expression and low methylation levels. This was for instance observed for some keratin genes. Tumor cases could be grouped into four subgroups, termed epitypes, by their DNA methylation profiles. One epitype was influenced by the presence of infiltrating immune cells, two epitypes were mainly composed of non-muscle invasive tumors, and the remaining epitype of muscle invasive tumors. The polycomb complex protein EZH2 that blocks differentiation in embryonic stem cells showed increased expression both at the mRNA and protein levels in the muscle invasive epitype, together with methylation of polycomb target genes and HOX genes. Our data highlights HOX gene silencing and EZH2 expression as mechanisms to promote a more undifferentiated and aggressive state in UC.
2012-08-31 | GSE33510 | GEO
Project description:We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes and tumor suppressor genes. In contrast, we also identified genes with copy number gains, high expression and low methylation levels. This was for instance observed for some keratin genes. Tumor cases could be grouped into four subgroups, termed epitypes, by their DNA methylation profiles. One epitype was influenced by the presence of infiltrating immune cells, two epitypes were mainly composed of non-muscle invasive tumors, and the remaining epitype of muscle invasive tumors. The polycomb complex protein EZH2 that blocks differentiation in embryonic stem cells showed increased expression both at the mRNA and protein levels in the muscle invasive epitype, together with methylation of polycomb target genes and HOX genes. Our data highlights HOX gene silencing and EZH2 expression as mechanisms to promote a more undifferentiated and aggressive state in UC. The study was conducted on genomic DNA from 150 primary fresh-frozen urothelial carcinoma tumors selected to have equal representation of stages Ta, T1 and T2>. The design also included four fully methylated and four unmethylated hybridization controls as well as 7 Normal urothelium samples. One tumor sample (UC_0556_1) was included as a technical replicate in each of four bisulfite treatment batches. The samples were bisulfite treated and hybridized to Illumina Human Methylation27 Bead Chip arrays according to manufacturers instructions at the SCIBLU Genomics Centre at Lund University, Sweden. Note: Illumina methylation data set comprises total of 168 samples (raw data), but 156 samples (processed data), derived from primary urothelial carcinoma samples. See README.txt for details of the 12 samples not included in the final, processed data.
2012-08-31 | E-GEOD-33510 | biostudies-arrayexpress
Project description:To investigate the mechanism of annual rhythms in Japanese cedar, annual time series samples were collected from the cuttings planted in natural condition. Also, to investigate the effects of photoperiod and temperature during transition to dormancy, the samples of cuttings grown in the controlled-environmental chamber were analyzed by a microarray.
2021-01-31 | GSE77155 | GEO
Project description:Seasonal cycles of light, temperature and precipitation provide signals that set the timing of gene expression and growth for trees. Conifers possess evergreen needles to sense and respond to year-round external signals. We monitored gene activity in Douglas-fir needles for one year and found that gene expression is dependent on light at daily and annual scales. The majority of rhythmic genes achieve maximum activity +/- 2 hours from sunrise and sunset, and +/- 20 days from the winter and summer solstices. Remarkably, the dormant period is characterized by significant gene activation, with thousands of genes achieving peak activity. This study identifies annual gene rhythms in conifers needles, and provides a framework for identifying genes that respond to other environmental cues. Background: Perennial growth in plants is the product of interdependent cycles of daily and annual stimuli that induce cycles of growth and dormancy. In conifers, needles are the key perennial organ that integrates daily and seasonal signals from light, temperature, and water availability. To understand the relationship between seasonal rhythms and seasonal gene expression responses in conifers, we examined diurnal and circannual needle mRNA accumulation in Douglas-fir (Pseudotsuga menziesii) needles at diurnal and circannual scales. Using mRNA sequencing, we sampled 6.1x10^9 microreads from 19 trees and constructed a de novo pan-transcriptome reference that includes 173,882 tree-derived transcripts. Using this reference, we mapped RNA-Seq reads from 179 samples that capture daily, seasonal, and annual variation. Results: We identified 12,042 diurnally-cyclic transcripts, 9,299 of which showed homology to annotated genes from other plant genomes, including angiosperm core clock genes. Annual analysis revealed 21,225 annually-cyclic transcripts, 17,335 of which showed homology to annotated genes from other plant genomes. The timing of maximum gene expression is associated with light quality at diurnal and photoperiod at annual scales, with two-thirds of transcripts reaching maximum expression +/- 2 hours from sunrise and sunset, and half reaching maximum expression +/- 20 days from winter and summer solstices. Comparison to published microarray-based gene expression studies in spruce (Picea) show that the rank order of expression for 760 putatively orthologous genes was significantly preserved, highlighting the generality of our findings. Conclusions: This finding highlights the extensive annual and seasonal transcriptome variability demonstrated in conifer needles. At these temporal scales, 29% of expressed transcripts showed a significant diurnal rhythm, and 58.7% showed a significant circannual rhythm. Remarkably, thousands of genes reach their annual peak activity during winter dormancy, a time of metabolic stasis. Photoperiod appears to be a dominant driver of annual transcription patterns in Douglas-fir, and these results may be general for predicting rhythmic transcription patterns in emerging gymnosperm models.
2017-01-04 | GSE93067 | GEO
Project description:Seasonal cycles of light, temperature and precipitation provide signals that set the timing of gene expression and growth for trees. Conifers possess evergreen needles to sense and respond to year-round external signals. We monitored gene activity in Douglas-fir needles for one year and found that gene expression is dependent on light at daily and annual scales. The majority of rhythmic genes achieve maximum activity +/- 2 hours from sunrise and sunset, and +/- 20 days from the winter and summer solstices. Remarkably, the dormant period is characterized by significant gene activation, with thousands of genes achieving peak activity. This study identifies annual gene rhythms in conifers needles, and provides a framework for identifying genes that respond to other environmental cues. Background: Perennial growth in plants is the product of interdependent cycles of daily and annual stimuli that induce cycles of growth and dormancy. In conifers, needles are the key perennial organ that integrates daily and seasonal signals from light, temperature, and water availability. To understand the relationship between seasonal rhythms and seasonal gene expression responses in conifers, we examined diurnal and circannual needle mRNA accumulation in Douglas-fir (Pseudotsuga menziesii) needles at diurnal and circannual scales. Using mRNA sequencing, we sampled 6.1x10^9 microreads from 19 trees and constructed a de novo pan-transcriptome reference that includes 173,882 tree-derived transcripts. Using this reference, we mapped RNA-Seq reads from 179 samples that capture daily, seasonal, and annual variation. Results: We identified 12,042 diurnally-cyclic transcripts, 9,299 of which showed homology to annotated genes from other plant genomes, including angiosperm core clock genes. Annual analysis revealed 21,225 annually-cyclic transcripts, 17,335 of which showed homology to annotated genes from other plant genomes. The timing of maximum gene expression is associated with light quality at diurnal and photoperiod at annual scales, with two-thirds of transcripts reaching maximum expression +/- 2 hours from sunrise and sunset, and half reaching maximum expression +/- 20 days from winter and summer solstices. Comparison to published microarray-based gene expression studies in spruce (Picea) show that the rank order of expression for 760 putatively orthologous genes was significantly preserved, highlighting the generality of our findings. Conclusions: This finding highlights the extensive annual and seasonal transcriptome variability demonstrated in conifer needles. At these temporal scales, 29% of expressed transcripts showed a significant diurnal rhythm, and 58.7% showed a significant circannual rhythm. Remarkably, thousands of genes reach their annual peak activity during winter dormancy, a time of metabolic stasis. Photoperiod appears to be a dominant driver of annual transcription patterns in Douglas-fir, and these results may be general for predicting rhythmic transcription patterns in emerging gymnosperm models.
2017-01-04 | GSE93066 | GEO