| 1. |
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| 2. |
- Atienza-Párraga, Alba, et al.
(författare)
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Epigenomic re-configuration of primary multiple myeloma underlies the synergistic effect of combined DNMT and EZH2 inhibition.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is characterized by an overexpression of EZH2 and a subsequent increase in H3K27me3-mediated silencing. However, the genome-wide redistribution of this mark in context with other epigenetic tags remains largely unexplored. Here, we show that EZH2 physically interacts with DNMT1 and that combined inhibition leads to a reduced G2/M arrest and increased apoptosis in MM. In addition, we present a catalogue of the genomic regulatory regions in normal plasma cells (NPC) as defined by their individual combination of histone marks. We used ChIP-seq and ATAC-seq data to generate whole-genome NPC chromatin annotations which we further analysed using DNA methylation arrays and RNA-seq. Comparison between NPC and MM demonstrated that, despite the global hypomethylation, enhancers show a tendency towards a higher DNA methylation levels in MM, whereas Polycomb and heterochromatic sites, highly methylated in NPC, show intermediate levels of the mark. Across all examined regulatory regions, 5-azacytidine treatment strongly reduced DNA methylation in MM. Furthermore, we find an extensive re-structuration of the global histone patterns in MM. We noticed a widespread increase in H3K27me3 except at active TSSs/promoters and enhancers, where we found a selective gain of the mark, suggestive of a directed silencing. In contrast, poised TSSs lose H3K27me3 and gain the activation mark H3K27ac, reflecting potential activation. Taken together, we present a comprehensive map of the epigenomic changes in MM as compared to NPC and provide insights into the interplay between EZH2 and DNMT1 in MM.
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| 3. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 4. |
- Carlevaro-Fita, J, et al.
(författare)
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Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis
- 2020
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1, s. 56-
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Tidskriftsartikel (refereegranskat)abstract
- Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.
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| 5. |
- Cavalli, Marco, et al.
(författare)
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A Multi-Omics Approach to Liver Diseases : Integration of Single Nuclei Transcriptomics with Proteomics and HiCap Bulk Data in Human Liver
- 2020
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Ingår i: Omics. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 24:4, s. 180-194
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Tidskriftsartikel (refereegranskat)abstract
- The liver is the largest solid organ and a primary metabolic hub. In recent years, intact cell nuclei were used to perform single-nuclei RNA-seq (snRNA-seq) for tissues difficult to dissociate and for flash-frozen archived tissue samples to discover unknown and rare cell subpopulations. In this study, we performed snRNA-seq of a liver sample to identify subpopulations of cells based on nuclear transcriptomics. In 4282 single nuclei, we detected, on average, 1377 active genes and we identified seven major cell types. We integrated data from 94,286 distal interactions (p < 0.05) for 7682 promoters from a targeted chromosome conformation capture technique (HiCap) and mass spectrometry proteomics for the same liver sample. We observed a reasonable correlation between proteomics and in silico bulk snRNA-seq (r = 0.47) using tissue-independent gene-specific protein abundancy estimation factors. We specifically looked at genes of medical importance. The DPYD gene is involved in the pharmacogenetics of fluoropyrimidine toxicity and some of its variants are analyzed for clinical purposes. We identified a new putative polymorphic regulatory element, which may contribute to variation in toxicity. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and we investigated all known risk genes. We identified a complex regulatory landscape for the SLC2A2 gene with 16 candidate enhancers. Three of them harbor somatic motif breaking and other mutations in HCC in the Pan Cancer Analysis of Whole Genomes dataset and are candidates to contribute to malignancy. Our results highlight the potential of a multi-omics approach in the study of human diseases.
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| 6. |
- Cavalli, Marco, et al.
(författare)
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Single Nuclei Transcriptome Analysis of Human Liver with Integration of Proteomics and Capture Hi-C Bulk Tissue Data
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Tidskriftsartikel (refereegranskat)abstract
- The liver is the largest solid organ and a primary metabolic hub. In recent years, intact cell nuclei were used to perform single-nuclei RNA-seq (snRNA-seq) for tissues difficult to dissociate and for flash-frozen archived tissue samples to discover unknown and rare cell sub-populations. In this study, we performed snRNA-seq of a liver sample to identify sub-populations of cells based on nuclear transcriptomics. In 4,282 single nuclei we detected on average 1,377 active genes and we identified seven major cell types. We integrated data from 94,286 distal interactions (p<0.05) for 7,682 promoters from a targeted chromosome conformation capture technique (HiCap) and mass spectrometry (MS) proteomics for the same liver sample. We observed a reasonable correlation between proteomics and in silico bulk snRNA-seq (r=0.47) using tissue-independent gene-specific protein abundancy estimation factors. We specifically looked at genes of medical importance. The DPYD gene is involved in the pharmacogenetics of fluoropyrimidines toxicity and some of its variants are analyzed for clinical purposes. We identified a new putative polymorphic regulatory element, which may contribute to variation in toxicity. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and we investigated all known risk genes. We found a complex regulatory network for the SLC2A2 gene with 16 candidate enhancers. Three of them harbor somatic motif breaking and other mutations in HCC in the Pan Cancer Analysis of Whole Genomes dataset and are candidates to contribute to malignancy. Our results highlight the potential of a multi-omics approach in the study of human diseases.
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| 7. |
- Cavalli, Marco, et al.
(författare)
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The Thioesterase ACOT1 as a Regulator of Lipid Metabolism in Type 2 Diabetes Detected in a Multi-Omics Study of Human Liver
- 2021
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Ingår i: Omics. - : Mary Ann Liebert. - 1536-2310 .- 1557-8100. ; 25:10, s. 652-659
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is characterized by pathophysiological alterations in lipid metabolism. One strategy to understand the molecular mechanisms behind these abnormalities is to identify cis-regulatory elements (CREs) located in chromatin-accessible regions of the genome that regulate key genes. In this study we integrated assay for transposase-accessible chromatin followed by sequencing (ATAC-seq) data, widely used to decode chromatin accessibility, with multi-omics data and publicly available CRE databases to identify candidate CREs associated with T2D for further experimental validations. We performed high-sensitive ATAC-seq in nine human liver samples from normal and T2D donors, and identified a set of differentially accessible regions (DARs). We identified seven DARs including a candidate enhancer for the ACOT1 gene that regulates the balance of acyl-CoA and free fatty acids (FFAs) in the cytoplasm. The relevance of ACOT1 regulation in T2D was supported by the analysis of transcriptomics and proteomics data in liver tissue. Long-chain acyl-CoA thioesterases (ACOTs) are a group of enzymes that hydrolyze acyl-CoA esters to FFAs and coenzyme A. ACOTs have been associated with regulation of triglyceride levels, fatty acid oxidation, mitochondrial function, and insulin signaling, linking their regulation to the pathogenesis of T2D. Our strategy integrating chromatin accessibility with DNA binding and other types of omics provides novel insights on the role of genetic regulation in T2D and is extendable to other complex multifactorial diseases.
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| 8. |
- Dabrowski, Michal J., et al.
(författare)
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Unveiling new interdependencies between significant DNA methylation sites, gene expression profiles and glioma patients survival
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- In order to find clinically useful prognostic markers for glioma patients' survival, we employed Monte Carlo Feature Selection and Interdependencies Discovery (MCFS-ID) algorithm on DNA methylation (HumanMethylation450 platform) and RNA-seq datasets from The Cancer Genome Atlas (TCGA) for 88 patients observed until death. The input features were ranked according to their importance in predicting patients' longer (400+ days) or shorter (<= 400 days) survival without prior classification of the patients. Interestingly, out of the 65 most important features found, 63 are methylation sites, and only two mRNAs. Moreover, 61 out of the 63 methylation sites are among those detected by the 450 k array technology, while being absent in the HumanMethylation27. The most important methylation feature (cg15072976) overlaps with the RE1 Silencing Transcription Factor (REST) binding site, and was confirmed to intersect with the REST binding motif in human U87 glioma cells. Six additional methylation sites from the top 63 overlap with REST sites. We found that the methylation status of the cg15072976 site affects transcription factor binding in U87 cells in gel shift assay. The cg15072976 methylation status discriminates <= 400 and 400+ patients in an independent dataset from TCGA and shows positive association with survival time as evidenced by Kaplan-Meier plots.
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| 9. |
- Diamanti, Klev, 1987-
(författare)
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Integrating multi-omics for type 2 diabetes : Data science and big data towards personalized medicine
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes (T2D) is a complex metabolic disease characterized by multi-tissue insulin resistance and failure of the pancreatic β-cells to secrete sufficient amounts of insulin. Cells recruit transcription factors (TF) to specific genomic loci to regulate gene expression that consequently affects the protein and metabolite abundancies. Here we investigated the interplay of transcriptional and translational regulation, and its impact on metabolome and phenome for several insulin-resistant tissues from T2D donors. We implemented computational tools and multi-omics integrative approaches that can facilitate the selection of candidate combinatorial markers for T2D.We developed a data-driven approach to identify putative regulatory regions and TF-interaction complexes. The cell-specific sets of regulatory regions were enriched for disease-related single nucleotide polymorphisms (SNPs), highlighting the importance of such loci towards the genomic stability and the regulation of gene expression. We employed a similar principle in a second study where we integrated single nucleus ribonucleic acid sequencing (snRNA-seq) with bulk targeted chromosome-conformation-capture (HiCap) and mass spectrometry (MS) proteomics from liver. We identified a putatively polymorphic site that may contribute to variation in the pharmacogenetics of fluoropyrimidines toxicity for the DPYD gene. Additionally, we found a complex regulatory network between a group of 16 enhancers and the SLC2A2 gene that has been linked to increased risk for hepatocellular carcinoma (HCC). Moreover, three enhancers harbored motif-breaking mutations located in regulatory regions of a cohort of 314 HCC cases, and were candidate contributors to malignancy.In a cohort of 43 multi-organ donors we explored the alternating pattern of metabolites among visceral adipose tissue (VAT), pancreatic islets, skeletal muscle, liver and blood serum samples. A large fraction of lysophosphatidylcholines (LPC) decreased in muscle and serum of T2D donors, while a large number of carnitines increased in liver and blood of T2D donors, confirming that changes in metabolites occur in primary tissues, while their alterations in serum consist a secondary event. Next, we associated metabolite abundancies from 42 subjects to glucose uptake, fat content and volume of various organs measured by positron emission tomography/magnetic resonance imaging (PET/MRI). The fat content of the liver was positively associated with the amino acid tyrosine, and negatively associated with LPC(P-16:0). The insulin sensitivity of VAT and subcutaneous adipose tissue was positively associated with several LPCs, while the opposite applied to branch-chained amino acids. Finally, we presented the network visualization of a rule-based machine learning model that predicted non-diabetes and T2D in an “unseen” dataset with 78% accuracy.
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| 10. |
- Diamanti, Klev, 1987-, et al.
(författare)
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Integration of whole-body [18F]FDG PET/MRI with non-targeted metabolomics can provide new insights on tissue-specific insulin resistance in type 2 diabetes
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Alteration of various metabolites has been linked to type 2 diabetes (T2D) and insulin resistance. However, identifying significant associations between metabolites and tissue-specific phenotypes requires a multi-omics approach. In a cohort of 42 subjects with different levels of glucose tolerance (normal, prediabetes and T2D) matched for age and body mass index, we calculated associations between parameters of whole-body positron emission tomography (PET)/magnetic resonance imaging (MRI) during hyperinsulinemic euglycemic clamp and non-targeted metabolomics profiling for subcutaneous adipose tissue (SAT) and plasma. Plasma metabolomics profiling revealed that hepatic fat content was positively associated with tyrosine, and negatively associated with lysoPC(P-16:0). Visceral adipose tissue (VAT) and SAT insulin sensitivity (Ki), were positively associated with several lysophospholipids, while the opposite applied to branched-chain amino acids. The adipose tissue metabolomics revealed a positive association between non-esterified fatty acids and, VAT and liver Ki. Bile acids and carnitines in adipose tissue were inversely associated with VAT Ki. Furthermore, we detected several metabolites that were significantly higher in T2D than normal/prediabetes. In this study we present novel associations between several metabolites from SAT and plasma with the fat fraction, volume and insulin sensitivity of various tissues throughout the body, demonstrating the benefit of an integrative multi-omics approach.
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