Two faces of bivalent domain regulate VEGFA responsiveness and angiogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA578281 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10307433_1.fastq.gz | Fastqsanger.gz | |||
| SRR10307433_2.fastq.gz | Fastqsanger.gz | |||
| SRR10307434_1.fastq.gz | Fastqsanger.gz | |||
| SRR10307434_2.fastq.gz | Fastqsanger.gz | |||
| SRR10307435_1.fastq.gz | Fastqsanger.gz |
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Project description:The bivalent domain at promoter region is a unique epigenetic feature poised for activation or repression during cell differentiation in embryonic stem cell. However, the function of bivalent domains in already differentiated cells remains exclusive. By profiling the epigenetic landscape of endothelial cells during VEGFA stimulation, we discovered that bivalent domains are widespread in endothelial cells and preferentially marked genes responsive to VEGFA. The bivalent domains responsive to VEGFA have more permissive chromatin environment comparing to other bivalent domains. The initial activation of bivalent genes depends on RNAPII pausing release induced by EZH1 rather than removal of H3K27me3. The later suppression of bivalent gene expression depended on KDM5A recruitment by its interaction with PRC2. Importantly, EZH1 promoted both in vitro and in vivo angiogenesis by upregulating EGR3, whereas KDM5A dampened angiogenesis. Collectively, this study demonstrated a novel dual function of bivalent domains in endothelial cells to control VEGF responsiveness and angiogenesis.
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Project description:The bivalent domain (BD) at promoter region is an unique epigenetic feature poised for activation or repression during cell differentiation in embryonic stem cell. However, the function of BDs in already differentiated cells remains exclusive. By profiling the epigenetic landscape of endothelial cells during VEGFA (vascular endothelial growth factor A) stimulation, we discovered that BDs are widespread in endothelial cells and preferentially marked genes responsive to VEGFA. The BDs responsive to VEGFA have more permissive chromatin environment comparing to other BDs. The initial activation of bivalent genes depends on RNAPII pausing release induced by EZH1 rather than removal of H3K27me3. The later suppression of bivalent gene expression depended on KDM5A recruitment by its interaction with PRC2. Importantly, EZH1 promoted both in vitro and in vivo angiogenesis by upregulating EGR3, whereas KDM5A dampened angiogenesis. Collectively, this study demonstrates a novel dual function of BDs in endothelial cells to control VEGF responsiveness and angiogenesis.
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Project description:SPRY4-IT1 (SPRY4 intronic transcript 1) is a long non-coding RNA (lncRNA) that was identified as a novel oncogene in various human cancers, including glioma. However, its function and the further mechanism in glioma remain largely unclear. Here, we aimed to investigate the role of SPRY4-IT1 in the development of glioma and its underlying molecular mechanism. We identify that SPRY4-IT1 is overexpressed in patients with glioma from the TCGA database and own cohort, and correlated with poor prognosis of patients. Then, loss of function and gain of function cell model were established by transfected with siRNA and pcDNA3.1 plasmid. SPRY4-IT1 promotes glioma cells proliferation by Cell Count Kit 8 assays and EdU assay in vitro, and xenograft tumor assays in vivo. RNA sequence was performed to compare the transcriptomes of U87 siSPRY4-IT1-NC and U87 siSPRY4-IT1 cells, and Gene Ontology (GO) enrichment analysis indicated angiogenesis is significantly enriched. HUVEC tube forming assays and Chick Embryo Chorioallantoic Membrane (CAM) assays confirmed that SPRY4-IT1 can induce angiogenesis of glioma in vitro and in vivo. Mechanistically, we identify that SPRY4-IT1 upregulates EZH2 expression by sponge miR-101-3p to induce VEGFA expression in glioma cells. Moreover, SPRY4-IT1 activates VEGFR2/AKT/ERK1/2 pathway in HUVECs by glioma cell-mediated. Rescue experiments were performed by co-transfected with SPRY4-IT1 and EZH2 overexpression plasmid in glioma cells, and confirmed that SPRY4-IT1 promotes cell proliferation and angiogenesis of glioma by miR-101-3p/EZH2/VEGFA signaling axis. Taken together, our studies clarify that SPRY4-IT1 upregulates EZH2 to induce VEGFA by sponge miR-101-3p to achieve cell proliferation and angiogenesis in glioma. Thus, these findings have provided insights into the prognosis prediction and therapeutic target of glioma.
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Project description:Trimethylation of histone 3 lysine 4 (H3K4me3) at promoters of actively transcribed genes is a universal epigenetic mark and a key product of Trithorax-Group action. Here we show that Mll2, one of the six Set1/Trithorax-type H3K4 methyltransferases in mammals, is required for trimethylation of bivalent promoters in mouse embryonic stem cells. Mll2 is bound to bivalent promoters but also to most active promoters, which do not require Mll2 for H3K4me3 or mRNA expression. In contrast, the Set1 complex (Set1C) subunit Cxxc1 is primarily bound to active but not bivalent promoters. This indicates that bivalent promoters rely on Mll2 for H3K4me3 whereas active promoters have more than one bound H3K4 methyltransferase including Set1C. Removal of Mll1, sister to Mll2, had almost no effect on any promoter unless Mll2 was also removed indicating functional back-up between these enzymes. Except for a subset, loss of H3K4me3 on bivalent promoters did not prevent responsiveness to retinoic acid thereby arguing against a priming model for bivalency. In contrast, we propose that Mll2 is the pioneer trimethyltransferase for promoter definition in the naM-CM-/ve epigenome and Polycomb-Group action on bivalent promoters blocks premature establishment of active, Set1C bound, promoters. ChIP-Seq to study MLL2 function using H3K4me3 (12 samples), H3K27me3 (4 samples), Pol2 (1 sample) or GFP (7 samples) antibody, and 6 RNA-Seq profiles
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