Project description:Epigenetic modifications and transcription factors form a chromatin code to regulate gene expression in many physiological and pathological processes. However, little is known about whether the environmental stimuli could interplay with this code and regulate the transcription and biological functions. Here, we interrogated the chromatin state of multiple epigenetic modifications and transcription factors during a time course of VEGF stimulation in the endothelial cells and found a broad change of transcriptome induced by VEGF. At the promoter-proximal regions, a unique epigenetic pattern of bivalent domain preferentially governed the part of transcriptome change by hijacking the EZH1 transcriptional activity. VEGF substantially altered the epigenetic landscape at enhancer regions and transcription factor chromatin occupancy across the genome, which significantly accounted for the change of VEGF-downstream gene expression. Moreover, by integrating a transcription-regulatory network of VEGF pathway, we discovered MAFs as a novel mater transcriptional factor controlling the VEGF transcriptional program and angiogenesis. Collectively, these results revealed the extracellular stimulus of VEGF in fact implements a significant reconfiguration of chromatin code that coordinately regulates the angiogenic response.
Project description:Epigenetic modifications and transcription factors form a chromatin code to regulate gene expression in many physiological and pathological processes. However, little is known about whether the environmental stimuli could interplay with this code and regulate the transcription and biological functions. Here, we interrogated the chromatin state of multiple epigenetic modifications and transcription factors during a time course of VEGF stimulation in the endothelial cells and found a broad change of transcriptome induced by VEGF. At the promoter-proximal regions, a unique epigenetic pattern of bivalent domain preferentially governed the part of transcriptome change by hijacking the EZH1 transcriptional activity. VEGF substantially altered the epigenetic landscape at enhancer regions and transcription factor chromatin occupancy across the genome, which significantly accounted for the change of VEGF-downstream gene expression. Moreover, by integrating a transcription-regulatory network of VEGF pathway, we discovered MAFs as a novel mater transcriptional factor controlling the VEGF transcriptional program and angiogenesis. Collectively, these results revealed the extracellular stimulus of VEGF in fact implements a significant reconfiguration of chromatin code that coordinately regulates the angiogenic response.
Project description:Alveolar soft part sarcoma (ASPS) is a rare soft part malignancy affecting adolescents and young adult. ASPS is characterized by its alveolar structure consisting of tumor cells and highly integrated vascular network, and its high metastatic potential indicates the importance of the prominent angiogenic activity of ASPS. Here we find that the expression of ASPSCR1-TFE3, the fusion transcription factor causatively associated with ASPS, is dispensable for in vitro tumor maintenance but required for in vivo tumor development via angiogenesis. ASPSCR1-TFE3 frequently associates with active enhancers including super-enhancers (SE) upon its DNA binding, and the loss of its expression induces dynamic modification of SE distribution related to genes belonging to the angiogenesis pathway. Using epigenomic CRISPR/dCas9 screening, we identify Pdgfb, Rab27a, Sytl2, and Vwf as critical target genes associated with reduced enhancer activities due to the ASPSCR1-TFE3 loss. ASPSCR1-TFE3 thus orchestrates higher ordered angiogenesis via enhanced intracellular trafficking of angiogenic factors.
Project description:Alveolar soft part sarcoma (ASPS) is a rare soft part malignancy affecting adolescents and young adult. ASPS is characterized by its alveolar structure consisting of tumor cells and highly integrated vascular network, and its high metastatic potential indicates the importance of the prominent angiogenic activity of ASPS. Here we find that the expression of ASPSCR1-TFE3, the fusion transcription factor causatively associated with ASPS, is dispensable for in vitro tumor maintenance but required for in vivo tumor development via angiogenesis. ASPSCR1-TFE3 frequently associates with active enhancers including super-enhancers (SE) upon its DNA binding, and the loss of its expression induces dynamic modification of SE distribution related to genes belonging to the angiogenesis pathway. Using epigenomic CRISPR/dCas9 screening, we identify Pdgfb, Rab27a, Sytl2, and Vwf as critical target genes associated with reduced enhancer activities due to the ASPSCR1-TFE3 loss. ASPSCR1-TFE3 thus orchestrates higher ordered angiogenesis via enhanced intracellular trafficking of angiogenic factors.
Project description:Alveolar soft part sarcoma (ASPS) is a rare soft part malignancy affecting adolescents and young adult. ASPS is characterized by its alveolar structure consisting of tumor cells and highly integrated vascular network, and its high metastatic potential indicates the importance of the prominent angiogenic activity of ASPS. Here we find that the expression of ASPSCR1-TFE3, the fusion transcription factor causatively associated with ASPS, is dispensable for in vitro tumor maintenance but required for in vivo tumor development via angiogenesis. ASPSCR1-TFE3 frequently associates with active enhancers including super-enhancers (SE) upon its DNA binding, and the loss of its expression induces dynamic modification of SE distribution related to genes belonging to the angiogenesis pathway. Using epigenomic CRISPR/dCas9 screening, we identify Pdgfb, Rab27a, Sytl2, and Vwf as critical target genes associated with reduced enhancer activities due to the ASPSCR1-TFE3 loss. ASPSCR1-TFE3 thus orchestrates higher ordered angiogenesis via enhanced intracellular trafficking of angiogenic factors. We used microarrays to detail the global program of gene expression in mouse and human ASPS cells.
Project description:Alveolar soft part sarcoma (ASPS) is a rare soft part malignancy affecting adolescents and young adult. ASPS is characterized by its alveolar structure consisting of tumor cells and highly integrated vascular network, and its high metastatic potential indicates the importance of the prominent angiogenic activity of ASPS. Here we find that the expression of ASPSCR1-TFE3, the fusion transcription factor causatively associated with ASPS, is dispensable for in vitro tumor maintenance but required for in vivo tumor development via angiogenesis. ASPSCR1-TFE3 frequently associates with active enhancers including super-enhancers (SE) upon its DNA binding, and the loss of its expression induces dynamic modification of SE distribution related to genes belonging to the angiogenesis pathway. Using epigenomic CRISPR/dCas9 screening, we identify Pdgfb, Rab27a, Sytl2, and Vwf as critical target genes associated with reduced enhancer activities due to the ASPSCR1-TFE3 loss. ASPSCR1-TFE3 thus orchestrates higher ordered angiogenesis via enhanced intracellular trafficking of angiogenic factors. We used microarrays to detail the global program of gene expression in mouse and human ASPS cells.
Project description:In plants, environmental stimuli trigger rapid transcriptional reprogramming of relevant gene suites. Regulation occurs down to the local chromatin landscape of the genes, and while epigenetic modifications proceed in a manner dependent on specific organ and tissue contexts, detailed investigations at this level remain limited. To better understand the organ specificity of dynamic chromatin modifications in response to external signals, we treated nitrogen-limited tomato seedlings with a supply of nitrate and measured the genome-wide changes of four histone marks, the permissive histone marks H3K27ac, H3K4me3, and H3K36me3 and repressive mark H3K27me3, in shoots and roots separately. We observed dynamic histone acetylation and methylation events which are largely organ-specific in scope at functionally relevant gene loci. Integration of transcriptomic and epigenomic datasets generated from the same tissue samples revealed largely syngenetic relations between changes in transcript levels and histone modifications, with the exception of H3K27me3 where an increased level at genes up-regulated in response to nitrate supply is observed in only the shoots. This non-canonical pattern of H3K27me3 deposition could possibly function to prevent over-expression of certain activated genes. To study the determinant roles of histone code in predicting gene regulation at the genome-wide level we applied a machine learning approach. While gene regulation could be best predicted using all four histone marks together, we observed different rules regarding the importance of individual histone marks between shoots, where H3K36me3 is the most successful mark in predicting gene activation and repression events, and the roots, where H3K4me3 is the strongest individual predictor. In summary, our integrated study substantiates a view that during plant environmental responses, the histone code dynamics that govern relationships between chromatin modification and gene regulation are highly dependent on tissue specific contexts.