Spatial clustering and common regulatory elements lead to TGF-β induced concerted gene expression
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PROVIDER: PRJNA503562 | ENA |
REPOSITORIES: ENA
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Project description:Cellular responses require temporally concerted transcriptional regulation of multiple genes. A single-input-module motif with one transcription factor regulating multiple target genes can generate the coordinated gene expression. In eukaryotic cells, the local environment of a gene characterized by histone modifications, DNA methylations, and the three-dimensional chromosome structure also regulates its transcriptional activity. To examine how the local environment and transcriptional factor regulation is coupled, we performed combined analysis of time-course RNA-seq data of TGF-β treated MCF10A cells and corresponding epigenome and Hi-C data. We discovered, genes co-regulated by a common transcription factor has tendency to be close both in the linear DNA sequence and spatially. Specifically, we identified local spatial organization of over a hundred of AP1-regulated genes, and competition between hetero- and homo-dimeric AP1 fine-tunes the complex structure leading to differential expression of downstream genes sharing similar local environment. We suggest this spatial organization as a general regulation principle.
2019-01-30 | GSE122093 | GEO
Project description:Complex multicellular organisms have evolved numerous cell types with many different functions. Comparative transcriptomic data yields valuable insights into cell type, tissue, and organ evolution. However, interpreting this data requires understanding how transcriptomes evolve. A particularly difficult problem is that cell type transcriptomes may not evolve independently, a key assumption of most evolutionary analyses. Non-independence of cell types can occur when cell types share regulatory mechanisms. This leads to concerted evolution in gene expression across different cell types, confounding efforts to unravel the history of cell type evolution, and identify cell type-specific patterns of expression. Here we present a statistical model to estimate the level of concerted transcriptome evolution and apply it to published and new data. The results indicate that tissues undergo pervasive concerted evolution in gene expression. Tissues related by morphology or developmental lineage exhibit higher levels of concerted evolution. Concerted evolution also causes tissues from the same species to be more similar in gene expression to each other than to homologous tissues in another species. This result may explain why some tissue transcriptomes cluster by species rather than homology. Our analysis of bird skin appendages data suggests levels of concerted evolution also varies with phylogenetic age of the tissue. Our study illustrates the importance of accounting for concerted evolution when interpreting comparative transcriptome data, and should serve as a foundation for future investigations of cell type evolution.
2017-10-13 | GSE89040 | GEO
Project description:Many cellular responses to surrounding cues require temporally concerted transcriptional regulation of multiple genes. In prokaryotic cells, a single-input-module motif with one transcription factor regulating multiple target genes can generate coordinated gene expression. In eukaryotic cells, transcriptional activity of a gene is affected by not only transcription factors but also the epigenetic modifications and three-dimensional chromosome structure of the gene. To examine how local gene environment and transcription factor regulation are coupled, we performed a combined analysis of time-course RNA-seq data of TGF-β treated MCF10A cells and related epigenomic and Hi-C data. Using Dynamic Regulatory Events Miner (DREM), we clustered differentially expressed genes based on gene expression profiles and associated transcription factors. Genes in each class have similar temporal gene expression patterns and share common transcription factors. Next, we defined a set of linear and radial distribution functions, as used in statistical physics, to measure the distributions of genes within a class both spatially and linearly along the genomic sequence. Remarkably, genes within the same class despite sometimes being separated by tens of million bases (Mb) along genomic sequence show a significantly higher tendency to be spatially close despite sometimes being separated by tens of Mb along the genomic sequence than those belonging to different classes do. Analyses extended to the process of mouse nervous system development arrived at similar conclusions. Future studies will be able to test whether this spatial organization of chromosomes contributes to concerted gene expression.
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Project description:Multipotent progenitors (MPP) and common dendritic cell progenitors (CDP) were obtained from mouse bone marrow, followed by in vitro culture with a specific cytokine cocktail and FACS sorting (Felker et al., 2010; Sere et al., 2012). Cells were treated with 10 ng/ml recombinant human TGF-b1 (R&D Systems, Minneapolis, USA) for 2, 4, 8, 12 and 24 h as described (Felker et al., 2010) or left untreated. Untreated multipotent progenitor (MPP) - MPP_0h_1 - MPP_0h_2 - MPP_0h_3 TGF-beta1 treated (2 hours) MPP - MPP_2h_1 - MPP_2h_2 - MPP_2h_3 TGF-beta1 treated (4 hours) MPP - MPP_4h_1 - MPP_4h_2 - MPP_4h_3 TGF-beta1 treated (8 hours) MPP - MPP_8h_1 - MPP_8h_2 - MPP_8h_3 TGF-beta1 treated (12 hours) MPP - MPP_12h_1 - MPP_12h_2 - MPP_12h_3 TGF-beta1 treated (24 hours) MPP - MPP_24h_1 - MPP_24h_2 - MPP_24h_3 Untreated common dendritic cell progenitor (CDP) - CDP_0h_1 - CDP_0h_2 - CDP_0h_3 TGF-beta1 treated (2 hours) CDP - CDP_2h_1 - CDP_2h_2 - CDP_2h_3 TGF-beta1 treated (4 hours) CDP - CDP_4h_1 - CDP_4h_2 - CDP_4h_3 TGF-beta1 treated (8 hours) CDP - CDP_8h_1 - CDP_8h_2 - CDP_8h_3 TGF-beta1 treated (12 hours) CDP - CDP_12h_1 - CDP_12h_2 - CDP_12h_3 TGF-beta1 treated (24 hours) CDP - CDP_24h_1 - CDP_24h_2 - CDP_24h_3
2014-04-15 | E-GEOD-46109 | biostudies-arrayexpress
Project description:Lead-seq: transcriptome-wide in vivo structure probing with lead
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Project description:Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional corepressor SKI, which is a negative regulator of TGF-β signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-β responses, in both knockin cells expressing an SGS mutation, and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.
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Project description:High blood lead (BPb) levels in children and elevated soil and dust arsenic, cadmium, and lead were previously found in Torreón, northern Mexico, host to the world's fourth largest lead-zinc metal smelter. The objectives of this study were to determine spatial distributions of adolescents with higher BPb and creatinine-corrected urine total arsenic, cadmium, molybdenum, thallium, and uranium around the smelter. Cross-sectional study of 512 male and female subjects 12-15 years of age was conducted. We measured BPb by graphite furnace atomic absorption spectrometry and urine trace elements by inductively coupled plasma-mass spectrometry, with dynamic reaction cell mode for arsenic. We constructed multiple regression models including sociodemographic variables and adjusted for subject residence spatial correlation with spatial lag or error terms. We applied local indicators of spatial association statistics to model residuals to identify hot spots of significant spatial clusters of subjects with higher trace elements. We found spatial clusters of subjects with elevated BPb (range 3.6-14.7??g/dl) and urine cadmium (0.18-1.14??g/g creatinine) adjacent to and downwind of the smelter and elevated urine thallium (0.28-0.93??g/g creatinine) and uranium (0.07-0.13??g/g creatinine) near ore transport routes, former waste, and industrial discharge sites. The conclusion derived from this study was that spatial clustering of adolescents with high BPb and urine cadmium adjacent to and downwind of the smelter and residual waste pile, areas identified over a decade ago with high lead and cadmium in soil and dust, suggests that past and/or present plant operations continue to present health risks to children in those neighborhoods.
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Project description:Enzymatic citrullination of latency-associated peptide of TGF beta1 by PAD2
2016-10-04 | MSV000080224 | MassIVE
Project description:The purpose of this study was to clarify the possible mechanism of common carp brain injury after exposure to lead through transcriptome analysis. Transcriptome analysis showed that 2141 differentially expressed genes were identified. Among these, 502 genes were up-regulated and 1639 genes were down-regulated. Meanwhile, GO enrichment analysis showed Transport, biological_process, DNA-templated (regulation of transcription) and signal transduction contained the most differential genes in the biological process. Furthermore, KEGG pathway enrichment analysis showed Ion channels, GnRH signaling pathway, cell adhesion molecules, Wnt signaling pathway, and calcium signaling pathway were significantly enriched. In addition, 10 differentially expressed genes were selected for qRT-PCR detection, and the results demonstrated that the selected genes exhibited the same trends with the RNA-Seq results, which indicates the transcriptome sequencing data is reliable. In conclusion, the above results provide a theoretical basis for clarifying the relationship between lead exposure and brain injury in common carp and for further studying of the genes related to lead poisoning.
2023-05-28 | GSE151339 | GEO
Project description:MS analysis of proteins interacting with PKA and TGF-β1 in HEK293T cells. MS analysis of immunoprecipitated TGF-β1 in HEK293T cells with TGF-β1 overexpression.
2022-06-28 | PXD031801 | Pride