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- Noguchi, S, et al.
(författare)
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FANTOM5 CAGE profiles of human and mouse samples
- 2017
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Ingår i: Scientific data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4, s. 170112-
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Tidskriftsartikel (refereegranskat)abstract
- In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
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| 5. |
- Alhendi, AMN, et al.
(författare)
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Promoter Usage and Dynamics in Vascular Smooth Muscle Cells Exposed to Fibroblast Growth Factor-2 or Interleukin-1β
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 13164-
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Tidskriftsartikel (refereegranskat)abstract
- Smooth muscle cells (SMC) in blood vessels are normally growth quiescent and transcriptionally inactive. Our objective was to understand promoter usage and dynamics in SMC acutely exposed to a prototypic growth factor or pro-inflammatory cytokine. Using cap analysis gene expression (FANTOM5 project) we report differences in promoter dynamics for immediate-early genes (IEG) and other genes when SMC are exposed to fibroblast growth factor-2 or interleukin-1β. Of the 1871 promoters responding to FGF2 or IL-1β considerably more responded to FGF2 (68.4%) than IL-1β (18.5%) and 13.2% responded to both. Expression clustering reveals sets of genes induced, repressed or unchanged. Among IEG responding rapidly to FGF2 or IL-1β were FOS, FOSB and EGR-1, which mediates human SMC migration. Motif activity response analysis (MARA) indicates most transcription factor binding motifs in response to FGF2 were associated with a sharp induction at 1 h, whereas in response to IL-1β, most motifs were associated with a biphasic change peaking generally later. MARA revealed motifs for FOS_FOS{B,L1}_JUN{B,D} and EGR-1..3 in the cluster peaking 1 h after FGF2 exposure whereas these motifs were in clusters peaking 1 h or later in response to IL-1β. Our findings interrogating CAGE data demonstrate important differences in promoter usage and dynamics in SMC exposed to FGF2 or IL-1β.
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| 7. |
- Klein, S, et al.
(författare)
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DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C
- 2016
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Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 129:13, s. 2573-2585
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Tidskriftsartikel (refereegranskat)abstract
- Lymphangiogenesis plays a crucial role during development, in cancer metastasis and in inflammation. Activation of VEGFR-3 by VEGF-C is one of the main drivers of lymphangiogenesis, but the transcriptional events downstream of VEGFR-3 activation are largely unknown. Recently, we identified a wave of immediate early transcription factors (TF) upregulated in human lymphatic endothelial cells (LEC) within the first 30 to 80 min after VEGFR-3 activation. Expression of these TFs must be regulated by additional, pre-existing TFs, which are rapidly activated by VEGFR-3 signaling. Using TF activity analysis, we identified the homeobox TF HOXD10 to be specifically activated at early time points after VEGFR-3 stimulation, and to regulate expression of immediate early TFs, including NR4A1. Gain- and loss of function studies revealed that HOXD10 is involved in LEC migration and formation of cord-like structures. Furthermore, HOXD10 regulates expression of VE-cadherin, claudin-5 and e-NOS, and promotes lymphatic endothelial permeability. Taken together, these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells and in the control of lymphangiogenesis and permeability.
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| 8. |
- Mina, M, et al.
(författare)
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Promoter-level expression clustering identifies time development of transcriptional regulatory cascades initiated by ErbB receptors in breast cancer cells
- 2015
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5, s. 11999-
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Tidskriftsartikel (refereegranskat)abstract
- The analysis of CAGE (Cap Analysis of Gene Expression) time-course has been proposed by the FANTOM5 Consortium to extend the understanding of the sequence of events facilitating cell state transition at the level of promoter regulation. To identify the most prominent transcriptional regulations induced by growth factors in human breast cancer, we apply here the Complexity Invariant Dynamic Time Warping motif EnRichment (CIDER) analysis approach to the CAGE time-course datasets of MCF-7 cells stimulated by epidermal growth factor (EGF) or heregulin (HRG). We identify a multi-level cascade of regulations rooted by the Serum Response Factor (SRF) transcription factor, connecting the MAPK-mediated transduction of the HRG stimulus to the negative regulation of the MAPK pathway by the members of the DUSP family phosphatases. The finding confirms the known primary role of FOS and FOSL1, members of AP-1 family, in shaping gene expression in response to HRG induction. Moreover, we identify a new potential regulation of DUSP5 and RARA (known to antagonize the transcriptional regulation induced by the estrogen receptors) by the activity of the AP-1 complex, specific to HRG response. The results indicate that a divergence in AP-1 regulation determines cellular changes of breast cancer cells stimulated by ErbB receptors.
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| 11. |
- Ehrlund, A, et al.
(författare)
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Transcriptional Dynamics During Human Adipogenesis and Its Link to Adipose Morphology and Distribution
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:1, s. 218-230
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Tidskriftsartikel (refereegranskat)abstract
- White adipose tissue (WAT) can develop into several phenotypes with different pathophysiological impact on type 2 diabetes. To better understand the adipogenic process, the transcriptional events that occur during in vitro differentiation of human adipocytes were investigated and the findings linked to WAT phenotypes. Single-molecule transcriptional profiling provided a detailed map of the expressional changes of genes, enhancers, and long noncoding RNAs, where different types of transcripts share common dynamics during differentiation. Common signatures include early downregulated, transient, and late induced transcripts, all of which are linked to distinct developmental processes during adipogenesis. Enhancers expressed during adipogenesis overlap significantly with genetic variants associated with WAT distribution. Transiently expressed and late induced genes are associated with hypertrophic WAT (few but large fat cells), a phenotype closely linked to insulin resistance and type 2 diabetes. Transcription factors that are expressed early or transiently affect differentiation and adipocyte function and are controlled by several well-known upstream regulators such as glucocorticosteroids, insulin, cAMP, and thyroid hormones. Taken together, our results suggest a complex but highly coordinated regulation of adipogenesis.
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| 14. |
- Backdahl, J., et al.
(författare)
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Long-Term Improvement in Aortic Pulse Wave Velocity After Weight Loss Can Be Predicted by White Adipose Tissue Factors
- 2018
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Ingår i: American Journal of Hypertension. - : Oxford University Press (OUP). - 0895-7061 .- 1941-7225. ; 31:4, s. 450-457
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Arterial stiffness, measured by pulse wave velocity (PWV), is linked to obesity, cardiovascular disease, and all-cause mortality. Short-term weight loss improves PWV, but the long-term effects are unknown. We investigated the effect of pronounced long-term weight loss on PWV and whether anthropometric/metabolic parameters and/or white adipose tissue (WAT) phenotype could predict this change in PWV. Eighty-two obese subjects were examined before and 2 years after Roux-en-Y gastric bypass. Analyses included anthropometrics, routine clinical chemistry, and hyperinsulinemic-euglycemic clamp. Arterial stiffness was measured as aortic PWV (aPWV) using the Arteriograph device. WAT mass and distribution were assessed by dual-X-ray absorptiometry. Baseline visceral and subcutaneous WAT samples were obtained to measure adipocyte cell size. Transcriptomic profiling of subcutaneous WAT was performed in a subset of subjects (n = 30). At the 2-year follow-up, there were significant decreases in body mass index (39.4 +/- 3.5 kg/m(2) vs. 26.6 +/- 3.4 kg/m(2); P < 0.0001) and aPWV (7.8 +/- 1.5 m/s vs. 7.2 +/- 1.4 m/s; P = 0.006). Multiple regression analyses showed that baseline subcutaneous adipocyte volume was associated with a reduction in aPWV (P = 0.014), after adjusting for confounders. Expression analyses of 52 genes implicated in arterial stiffness showed that only one, COL4A1, independently predicted improvements in aPWV after adjusting for confounders (P = 0.006). Bariatric surgery leads to long-term reduction in aPWV. This improvement can be independently predicted by subcutaneous adipocyte volume and WAT COL4A1 expression, which suggests that subcutaneous WAT has a role in regulating aPWV.
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| 16. |
- Ha, TJ, et al.
(författare)
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Identification of novel cerebellar developmental transcriptional regulators with motif activity analysis
- 2019
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Ingår i: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 20:1, s. 718-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe work of the FANTOM5 Consortium has brought forth a new level of understanding of the regulation of gene transcription and the cellular processes involved in creating diversity of cell types. In this study, we extended the analysis of the FANTOM5 Cap Analysis of Gene Expression (CAGE) transcriptome data to focus on understanding the genetic regulators involved in mouse cerebellar development.ResultsWe used the HeliScopeCAGE library sequencing on cerebellar samples over 8 embryonic and 4 early postnatal times. This study showcases temporal expression pattern changes during cerebellar development. Through a bioinformatics analysis that focused on transcription factors, their promoters and binding sites, we identified genes that appear as strong candidates for involvement in cerebellar development. We selected several candidate transcriptional regulators for validation experiments including qRT-PCR and shRNA transcript knockdown. We observed marked and reproducible developmental defects in Atf4, Rfx3, and Scrt2 knockdown embryos, which support the role of these genes in cerebellar development.ConclusionsThe successful identification of these novel gene regulators in cerebellar development demonstrates that the FANTOM5 cerebellum time series is a high-quality transcriptome database for functional investigation of gene regulatory networks in cerebellar development.
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| 17. |
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| 18. |
- Vacca, A, et al.
(författare)
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Conserved temporal ordering of promoter activation implicates common mechanisms governing the immediate early response across cell types and stimuli
- 2018
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Ingår i: Open biology. - : The Royal Society. - 2046-2441. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- The promoters of immediate early genes (IEGs) are rapidly activated in response to an external stimulus. These genes, also known as primary response genes, have been identified in a range of cell types, under diverse extracellular signals and using varying experimental protocols. Whereas genomic dissection on a case-by-case basis has not resulted in a comprehensive catalogue of IEGs, a rigorous meta-analysis of eight genome-wide FANTOM5 CAGE (cap analysis of gene expression) time course datasets reveals successive waves of promoter activation in IEGs, recapitulating known relationships between cell types and stimuli: we obtain a set of 57 (42 protein-coding) candidate IEGs possessing promoters that consistently drive a rapid but transient increase in expression over time. These genes show significant enrichment for known IEGs reported previously, pathways associated with the immediate early response, and include a number of non-coding RNAs with roles in proliferation and differentiation. Surprisingly, we also find strong conservation of the ordering of activation for these genes, such that 77 pairwise promoter activation orderings are conserved. Using the leverage of comprehensive CAGE time series data across cell types, we also document the extensive alternative promoter usage by such genes, which is likely to have been a barrier to their discovery until now. The common activation ordering of the core set of early-responding genes we identify may indicate conserved underlying regulatory mechanisms. By contrast, the considerably larger number of transiently activated genes that are specific to each cell type and stimulus illustrates the breadth of the primary response.
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| 19. |
- Yu, Nancy Yiu-Lin, et al.
(författare)
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Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium
- 2015
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 43:14, s. 6787-6798
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the normal state of human tissue transcriptome profiles is essential for recognizing tissue disease states and identifying disease markers. Recently, the Human Protein Atlas and the FANTOM5 consortium have each published extensive transcriptome data for human samples using Illumina-sequenced RNA-Seq and Heliscope-sequenced CAGE. Here, we report on the first large-scale complex tissue transcriptome comparison between full-length versus 5'-capped mRNA sequencing data. Overall gene expression correlation was high between the 22 corresponding tissues analyzed (R > 0.8). For genes ubiquitously expressed across all tissues, the two data sets showed high genome-wide correlation (91% agreement), with differences observed for a small number of individual genes indicating the need to update their gene models. Among the identified single-tissue enriched genes, up to 75% showed consensus of 7-fold enrichment in the same tissue in both methods, while another 17% exhibited multiple tissue enrichment and/or high expression variety in the other data set, likely dependent on the cell type proportions included in each tissue sample. Our results show that RNA-Seq and CAGE tissue transcriptome data sets are highly complementary for improving gene model annotations and highlight biological complexities within tissue transcriptomes. Furthermore, integration with image-based protein expression data is highly advantageous for understanding expression specificities for many genes.
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